N-substituted tricyclic 3-aminopyrazoles as inhibitors for the treatment of cell proliferative disorders

ABSTRACT

The invention is directed to N-substituted tricyclic 3-AMINOPYRAZOLE derivatives, which are useful as inhibitors of platelet-derived growth factor receptor (PDGF-R) kinase, and methods for the preparation of said derivatives. The present invention is further directed to pharmaceutical compositions comprising the compounds of the present invention and to methods for treating conditions such as tumors and other cell proliferative disorders.

CROSS REFERENCE

[0001] The present application claims priority under 35 U.S.C. § 119(e)from co-pending U.S. patent application Ser. No. 60/380,735, filed May15, 2002, which is incorporated herein by reference in its entirety andfor all purposes.

FIELD OF THE INVENTION

[0002] This invention relates to a novel series of N-substitutedtricyclic 3-aminopyrazole compounds and the use of such compounds totreat cell proliferative disorders, such as tumors, restenosis,rheumatoid arthritis, diabetic retinopathy, and the like. Moreparticularly, the compounds are inhibitors of the PDGF receptor tyrosinekinase.

BACKGROUND OF THE INVENTION

[0003] Accumulating evidence supports the concept that loss of growthcontrol of cancer cells involves perturbation of signaling pathways thatin the normal cell are controlled by growth regulatory factors.Platelet-derived growth factor (PDGF) is a connective tissue cellmitogen that has been implicated in tumorigenesis (Ostman and Heldin,Adv. Can. Res., 80:1-38, 2001, and references therein) as well as aprincipal player in the complex process of angiogenesis that is criticalfor tumor growth.

[0004] PDGF exerts its cellular effects through binding to its specificreceptor, PDGF-R. PDGF-R is a transmembrane receptor tyrosine kinase(RTK). It consists of two isozymes α and β. Each of these receptors hasan extracellular part featuring five immunoglobulin-like domains and anintracellular part with a tyrosine kinase domain. Both α andβ-containing receptors have been associated with mitogenic activity,stimulating edge ruffling and loss of stress fibers. Only theβ-containing receptors has been associated with chemotaxis and actinreorganization (Heldin, C -H, EMBO Journal 11:4251-4259,1992).

[0005] Binding of PDGF to PDGF-R results in dimerization of the twosubunits of the PDGF-R receptors, thereby allowing autophosphorylationof each subunit on specific tyrosine residues in the cytoplasmic domain.The autophosphorylation leads to increased kinase activity and producesdocking sites for a large number of signaling molecules with SH2domains, such as Grb2/Sos1, PLC-gamma, GAP, PI-3 kinase and Src. (Heldinet al., Biochem. Biophys. Acta 1378:F79-113, 1998, and referencestherein). Upon binding to PDGF-R, these SH2 domain-containing signalingmolecules initiate signal transduction pathways that are involved indifferent cellular responses such as cell proliferation, cell mobility,cell permeability or apoptosis.

[0006] PDGF has several important cellular effects in vivo. It regulatescell growth, differentiation, and migration during embryonaldevelopment, and plays a possible role in neuroprotection andregeneration. It also stimulates wound healing in adults. In addition,PDGF also has specialized functions in the vascular system as well as inthe homeostasis of connective tissue (Ostman and Heldin, Adv. Can. Res.,80:1-38, 2001, and references therein).

[0007] Overactivity of PDGF has been implicated in the pathogenesis of anumber of serious diseases, including cancers (glioma, lung, breast,colorectal, prostate, gastric and esophageal, leukemias and lymphomas),and other cell proliferative disorders, such as atherosclerosis,transplantation-induced vasculopathies, neointima formation, lungfibrosis, restenosis, pulmonary fibrosis, glomerulonephritis,glomerulosclerosis, congenital multicystic renal dysplasia, kidneyfibrosis, and rheumatoid arthritis (Ostman A, Heldin C H., Adv. CancerRes, 80:1-38,2001, and references therein).

[0008] A considerable body of direct and indirect experimental evidenceshowed that sustained tumor growth and metastasis areangiogenesis-dependent (see e.g., Hanahan, Science, 277:48-50, 1997).Angiogenesis is the development of new vasculature from preexistingblood vessels and/or circulating endothelial stem cells (see i.e.,Springer et al., 1998). Angiogenesis plays a vital role in manyphysiological processes, such as embryogenesis, wound healing andmenstruation. Angiogenesis also appears to be important in certainpathological events, such as solid tumor growth and metastasis,arthritis, psoriasis and diabetic retinopathy (Hanahan and Folkman,Cell, 86(3):353-364, 1996;).

[0009] Anti-angiogenic therapy is currently being studied as a way tointerfere with tumor growth. Indeed, numerous studies in animal modelshave demonstrated striking effects in tumor growth inhibition bytargeting angiogenic growth factors such as vascular endothelial growthfactor (VEGF), acidic and basic fibroblast growth factor (aFGF, bFGF)and PDGF. The receptors for VEGF and PDGF belong to one super family ofreceptor tyrosine kinases. Therefore, in addition to their role intreating other cell proliferative disorders, clinically useful PDGF-Rtyrosine kinase inhibitors are useful for antiangiogenic therapy and tocontrol tumor cell proliferation.

[0010] Small molecule inhibitors of the receptor tyrosine kinaseconstitute a novel class of drugs with large potential (Druker andLydon, J. Clin. Invest., 105:3-7, 2000, and references therein). Since1995, a number of small molecule inhibitors for PDGF receptorautophosphorylation have been characterized. Some examples are listedbelow.

[0011] JP 06087834 (Zimmermann) discloses N-phenyl-2-pyrimidine-aminederivatives which have tumor inhibitory activity and are useful fortreating tumors in warm-blooded animals including human beings.Derivatives of this group of compounds, compound CGP53716 (Buchdunger etal., PNAS, 92:2558-2562,1995) and compound STI-571 (Buchdunger et al.,Cancer Res, 56:100-4, 1996), have been shown to inhibit PDGF-Rautophosphorylation.

[0012] JP 11158149 (Kubo et al.) discloses quinoline derivatives for thetreatment of diseases such as tumors and diabetic retinopathy.Derivatives of this group of compounds, compound Ki6783 (Yagi et al.,Exp. Cell Res. 243:285-292, 1997) and compound Ki6896 (Yagi et al., Gen.Pharmacol. 31:765-773, 1998), have been shown to inhibit PDGF-Rautophosphorylation.

[0013] U.S. Pat. No. 5,932,580 (Levitzki et al.) discloses PDGF receptorkinase inhibitory compounds of the quinoxaline family includingTyrphostin, ATP-competitive inhibitors of the receptor kinase.

[0014] U.S. Pat. No. 5,409,930 (Spada, et al.) discloses bis mono-and/or bicyclic aryl and/or heteroaryl compounds exhibiting proteintyrosine kinase inhibition activity. Compound RPR101511A, a derivativeof this group of compound, has been shown to inhibit PDGF-Rautophosphorylation (Bilder et al., Circulation. 99(25):3292-9. 1999).

[0015] U.S. Pat. No. 5,563,173 (Yatsu, et al.) discloses a method ofinhibiting the proliferation of smooth muscle cells by sodium butyrate,which inhibits PDGF-R kinase activity.

[0016] U.S. Pat. No. 5,476,851 (Myers, et al.) disclosesPyrazolo[3,4-g]quinoxaline compounds, as PDGF receptor protein tyrosinekinase inhibitors.

[0017] Compound SU-6668, an ATP competitive inhibitor, has been shown toinhibit PDGF-R autophosphorylation (Laird, et al., Cancer Res.60:4152-4160, 2000].

[0018] WO01/79198 (Reich et al.) discloses amino-pyrazole compounds ofthe following formula that modulate and/or inhibit the activity ofprotein kinases.

[0019] WO0212242 (Fancelli et al.) discloses bicyclo-pyrazole compoundsthat are useful for treating diseases linked to disregulated proteinkinases.

[0020] Up to now, STI-571 (GLEEVEC) is the only compound to reach marketwith significant PDGFR activity, although it is not a selectiveantagonist of this enzyme. Therefore, PDGF-R remains an extremelyattractive target for the design of potent and selective small moleculeinhibitors that will represent an important new class of therapeuticagents for the treatment of tumors and other cell proliferativedisorders.

[0021] References to a number of substituted tricyclic pyrazolederivatives include those disclosing use as: inhibitors of tyrosinekinase activity (WO 99/17769, WO 99/17770); cyclin dependent kinasesinhibitors (WO 99/54308); selective estrogen receptor modulators (WO00/07996); analgesics (U.S. Pat. No. 4,420,476); prophylaxis and therapyof diseases caused by rhinoviruses (U.S. Pat. No. 4,220,776; U.S. Pat.No. 4,140,785); analgesics/anti-inflammatory activity (U.S. Pat. No.3,928,378; Schenone, Silvia et al. Farmaco (2000), 55(5), 383-388); cyancouplers for photographic dye (EP 0620489, JP 8022109); quinolines andnaphthyridines as drugs (JP 6092963); and immunomodulators (JP 6100561);and hypoglycemic agents (Reddy, R. Raja et al., Indian Journal ofHeterocyclic Chemistry (1998), 7(3), 189-192).

SUMMARY OF THE INVENTION

[0022] The present invention provides N-substituted tricyclic3-aminopyrazole derivatives as inhibitors of the PDGF receptor (PDGF-R)tyrosine kinase and the use of such compounds to treat cellproliferative disorders or disorders related to (i.e., associated withor implicating with) platelet-derived growth factor receptor (PDGF-R)such as such as tumors, restenosis, rheumatoid arthritis, diabeticretinopathy, and the like.

[0023] Illustrative of the invention is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and any of thecompounds of Formulae (I) and (II). Another illustration of theinvention is a process for making a pharmaceutical compositioncomprising mixing any of the compounds of Formulae (I) and (II) and apharmaceutically acceptable carrier. Another illustration of the presentinvention is a pharmaceutical composition prepared by mixing any of thecompounds of Formulae (I) and (II) and a pharmaceutically acceptablecarrier.

[0024] The present invention is further related to the use of a compoundof Formulae (I) and (II) for the treatment of a PDGF-R related disorderor a cell proliferative disorder in a subject comprising administeringto the subject a therapeutically effective amount of a compound ofFormulae (I) and (II). The disorder related to PDGF-R or a cellproliferative disorder is selected from neoplastic and other cellproliferative disorders. Preferably, said neoplastic disorder is acancer selected from a glioma cancer, a lung cancer, a breast cancer, acolorectal cancer, a prostate cancer, a gastric cancer, an esophagealcancer, a colon cancer, a pancreatic cancer, an ovarian cancer, amelanoma, a myelodiys plasia, a multiple myeloma, a leukemia and alymphoma, and said other cell proliferative disorder is selected fromatherosclerosis, transplantation-induced vasculopathies, neointimaformation, lung fibrosis, macular degeneration, restenosis, pulmonaryfibrosis, glomerulonephritis, glomerulosclerosis, congenital multicysticrenal dysplasia, kidney fibrosis, rheumatoid arthritis and diabeticretinopathy.

[0025] The invention is directed to a method of inhibiting the onset ofa disorder related to PDGF-R or a cell proliferative disorder in asubject comprising administering to the subject a prophylacticallyeffective amount of a compound of Formulae (I) and (II).

[0026] The invention further includes a combination therapy in treatingor inhibiting the onset of a disorder related to PDGF-R or a cellproliferative disorder in a subject. The combination therapy comprisesadministering to the subject a therapeutically or prophylacticallyeffective amount, respectively, of a compound of the invention and oneor more other anti-cell proliferation therapies including, but notlimited to, chemotherapy, radiation therapy, gene therapy andimmunotherapy.

[0027] The present invention also provides a method for the treatment ofa cell proliferative disorder, preferably restenosis, intimalhyperplasia, inflammation, or atherosclerosis in vessel walls,comprising the controlled delivery, by release from an intraluminalmedical device, of a compound of the invention in therapeutic effectiveamounts.

[0028] The present invention further provides a method of treating acell proliferative disorder in a subject, preferably, a neoplasticdisorder selected from a glioma cancer, a lung cancer, a breast cancer,a colorectal cancer, a prostate cancer, a gastric cancer, an esophagealcancer, a colon cancer, a pancreatic cancer, an ovarian cancer, amelanoma, a myelodysplasia, a multiple myeloma, a leukemia and alymphoma, comprising administering to the subject a therapeuticeffective amount of a compound of the invention conjugated to atargeting agent.

[0029] The present invention further provides a method for reducing orinhibiting the kinase activity of PDGF-R or c-Abl in a cell comprisingthe step of contacting the cell with a compound of Formulae (I) or (II).The present invention also provides a method of inhibiting the kinaseactivity of PDGF-R or c-Abl in a subject comprising the step ofadministering a compound of Formula (I) or (II) to the subject. Thepresent invention further provides a method of inhibiting cellproliferation in a cell comprising the step of contacting the cell witha compound of Formulae (I) or (II).

[0030] The present invention further provides a method of identifyingnovel PDGF-R kinase inhibitors. The method comprises the steps of:

[0031] (a) determining a three-dimensional structure of the compound ofFomulae (I) or (II) in the absence or presence of a polypeptidecomprising the PDGF-R kinase catalytic domain;

[0032] (b) analyzing the three-dimensional structure for the compoundalone or for the intermolecular interaction between said compound andPDGF-R;

[0033] (c) selecting a compound that mimics the structure for thecompound alone or incorporates the predictive interaction;

[0034] (d) synthesizing said designed compound; and

[0035] (e) determining the ability of the molecule to bind and inhibitPDGF-R kinase activity.

[0036] The present invention further provides a method of identifyingnovel c-Abl kinase inhibitors. The method comprises the steps of:

[0037] (a) determining a three-dimensional structure of the compound ofFormulae (I) or (II) in the absence or presence of a polypeptidecomprising the c-Abl kinase catalytic domain;

[0038] (b) analyzing the three-dimensional structure for the compoundalone or for the intermolecular interaction between said compound andc-Abl;

[0039] (c) selecting a compound that mimics the structure for thecompound alone or incorporates the predictive interaction;

[0040] (d) synthesizing said designed compound; and

[0041] (e) determining the ability of the molecule to bind and inhibitc-Abl kinase activity.

[0042] The present invention is further directed to processes for thepreparation of compounds of Formula (I) and compounds of Formula (II)

[0043] Other features and advantages of the invention will be apparentfrom the following detailed description of the invention thereof, andfrom the claims.

DETAILED DESCRIPTION OF THE INVENTION

[0044] The present invention relates to novel N-substituted tricyclic3-aminopyrazole derivatives, their synthesis and the use of saidcompounds for the treatment and/or prevention of PDGF-R relateddisorders, such as tumors, restenosis, rheumatoid arthritis, diabeticretinopathy, and the like.

[0045] 1. Formula (I)

[0046] The present invention is directed to compounds of Formula (I):

[0047] wherein,

[0048] n is an integer from 1 to 4;

[0049] R¹ is selected from the group consisting of hydrogen, loweralkyl, —OH, alkoxy, -oxo, —NH₂, —NH(alkyl) and —N(alkyl)₂;

[0050] is selected from the group consisting of an aryl, a five to sixmembered monocyclic heteroaryl, a nine to ten membered benzo-fusedheteroaryl, a nine to ten membered benzo-fused heterocycloalkyl group,and a nine to ten membered benzo-fused cycloalkyl group; wherein thebenzo-fused heteroaryl, benzo-fused heterocycloalkyl or benzo-fusedcycloalkyl group is attached to the molecule such that the phenyl ringis bound directly to the

[0051] portion of the molecule;

[0052] p is an integer from 0 to 2;

[0053] R² is selected from the group consisting of

[0054] , and —X-A¹-Y-A²; wherein,

[0055] X and Y are each independently absent or selected from the groupconsisting of —O—, —NH—, —N(alkyl)-, —S—, —SO—, —SO₂—, —OC(═O),—C(═O)O—, —NHC(═O)—, —N(alkyl)C(═O)—, —C(═O)NH—, —C(═O)N(alkyl)-,—OC(═O)O—, —NHC(═O)O—, —OC(═O)NH—, —N(alkyl)C(═O)O—, —OC(═O)N(alkyl)-,—NHC(═O)NH—, —NHC(═O)N(alkyl)-, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)N(alkyl)-, —NHSO₂—, —SO₂NH—, —N(alkyl)SO₂— and—SO₂N(alkyl)-;

[0056] A¹ is absent or selected from alkyl or alkenyl; A² is selectedfrom alkyl, alkenyl, or H; wherein, when A¹ or A² is alkyl or alkenyl,the alkyl or alkenyl group may be optionally substituted with one ormore groups independently selected from halogen, cyano, hydroxy, alkoxy,thio, halogenated alkoxy, —OC(═O)alkyl, —OC(═O)Oalkyl, amino,alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, dialkylamino,—NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)NH₂,—OC(═O)NHalkyl, -NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂;

[0057] is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl; wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, is optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, amino, thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy,halogenated alkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, ordialkylamino, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂;

[0058] q is an integer from 0 to 4;

[0059] R³ is selected from the group consisting of halogen, hydroxy,amino, thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy, halogenatedalkyloxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, ordialkylamino, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ and—OC(═O)N(alkyl)₂;

[0060] provided that the sum of p and q is an integer from 0 to 4;

[0061] L¹ is absent or selected from the group consisting of alkyl;

[0062] is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl;

[0063] or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof, useful for the treatment of aPDGF-R related disorders.

[0064] In formula (I), when

[0065] is a nine to ten membered benzo-fused heteroaryl, a nine to tenmembered benzo-fused heterocycloalkyl, or a nine to ten memberedbenzo-fused cycloalkyl group, the benzo-fused heteroaryl, benzo-fusedheterocycloalkyl, or benzo-fused cycloalkyl group is attached to themolecule such that the phenyl ring is bound directly to the

[0066] portion of the molecule at the carbons indicated as “x” and “y”.For example, wherein

[0067] is unsubstituted 3,4-methylenedioxyphenyl, the1,3-methylenedioxyphenyl group may be bound to the rest of the compoundof formula (I) to form a compound of the formula (Im), (In) or (Ip):

[0068] wherein the exact orientation would be evident from the structureor name of the compound prepared.

[0069] 1.a Embodiments of Formula (I)

[0070] In an embodiment of the present invention

[0071] is selected from the group consisting of phenyl, thienyl,pyridyl, pyrimidinyl, furyl, isoxazolyl, imidazolyl, pyrazolyl and3,4-methylenedioxyphenyl. Preferably

[0072] is selected form the group consisting of phenyl, thienyl and3,4-methylenedioxyphenyl. In another embodiment of the present invention

[0073] is selected form the group consisting of a five or six memberedheteroaryl. In another embodiment of the present invention

[0074] is selected from the group consisting of a nine or ten memberedbenzo-fused heteroaryl, a nine or ten membered benzo-fused cycloalkyl,and a nine or ten membered benzo-fused heterocycloalkyl.

[0075] In a preferred embodiment of the present invention R¹ is selectedfrom the group consisting of hydrogen, hydroxy, methyl, and oxo,preferably R¹ is hydrogen or methyl.

[0076] In an embodiment of the present invention n is an integer from 1to 2. In another embodiment of the present invention p is 0 and q is aninteger from 0 to 2. In yet another embodiment of the present inventionp is an integer from 1 to 2 and q is an integer from 0 to 1.

[0077] In an embodiment of the present invention, R² is

[0078] wherein X, A¹ and

[0079] are as defined herein. Preferably, X is O. In another embodimentof the present invention, X is O and

[0080] is a heterocycloalkyl or heteroaryl, wherein the heterocycloalkylor heteroaryl is optionally substituted with one to three substituentsindependently selected from halogen, alkoxy, hydroxy, amino, alkylaminoor dialkylamino.

[0081] In another embodiment of the present invention, R² is —X-A¹-Y-A²wherein X, A¹, Y, A² are as defined herein. Preferably, X and Y are eachindependently absent or O.

[0082] In an embodiment of the present invention, R³ is selected fromthe group consisting of alkoxy, halogen, amino, dialkylamino, loweralkyl, and hydroxy. Preferably, R³ is lower alkyl or lower alkoxy.

[0083] In an embodiment of the present invention L¹ is a lower alkyl,preferably methylene. In another embodiment of the present invention L¹is absent.

[0084] A preferred embodiment of the present invention,

[0085] is aryl, heteroaryl, cycloalkyl, or herterocycloalkyl. Preferably

[0086] is aryl or heteroaryl.

[0087] In an embodiment of the present invention is a compound ofFormula (Ia):

[0088] wherein n, R¹, p, R², q, R³, L¹ and

[0089] are as defined herein for Formula (I), or an optical isomer,enantiomer, diastereomer, racemate or pharmaceutically acceptable saltthereof.

[0090] Another preferred embodiment of the present invention is acompound of formula (I) wherein n is an integer from 1 to 2;

[0091] R¹ is hydrogen;

[0092] is selected from the group consisting of phenyl, a five to sixmembered heteroaryl and a nine to ten membered benzo-fusedheterocycloalkyl group; wherein the nine to ten membered benzo-fusedheterocycloalkyl group is attached to the molecule such that the phenylring is bound directly to the portion of the molecule; preferably,

[0093] is selected from the group consisting of phenyl, thienyl and1,3-benzodioxolyl;

[0094] p is an integer from 0 to 2;

[0095] R² is selected from the group consisting of di(loweralkyl)amino-alkoxy, lower alkyl-alkoxy, hydroxy substituted alkoxy and

[0096] wherein A¹ is selected from the group consisting of lower alkyl;wherein the lower alkyl is optionally substituted with one to twosubstituents independently selected from hydroxy, amino, alkylamino ordialkylamino; and wherein

[0097] is selected from the group consisting of a five or six memberedheteroaryl and a five or six membered heterocycloalkyl; wherein theheteroaryl or heterocycloalkyl is optionally substituted with one to twosubstituents independently selected from halogen, lower alkyl, loweralkoxy, amino, lower alkylamino or di(lower alkyl)amino; preferably, R²is selected from the group consisting of 3-dimethylamino-propoxy,3-methoxy-propoxy, 2,3-dihydroxy-n-propoxy, 3-hydroxy-propoxy,2-hydroxy-3-pyrrolid in-1-yl-propoxy and3-(4-methyl-piperazin-1-yl-propoxy;

[0098] q is an integer from 0 to 2;

[0099] R³ is selected from the group consisting of lower alkyl and loweralkoxy, and halogen; preferably, R³ is selected from the groupconsisting of methyl, methoxy, ethoxy.

[0100] L¹ is absent or lower alkyl, preferably, L¹ is absent or CH₂;

[0101] is selected from the group consisting of phenyl and a five or sixmembered heteroaryl group; wherein the phenyl or heteroaryl group isoptionally substituted with one to two substituents independentlyselected from halogen, lower alkyl, lower alkoxy or benzyloxy;preferably,

[0102] is selected from the group consisting of phenyl and pyridyl;wherein the phenyl is optionally substituted with one to twosubstituents independently selected from fluoro, chloro, methyl, methoxyor benzyloxy;

[0103] or an optical isomer, enantiomer, diastereomer, racemate orpharmaceutically acceptable salt thereof.

[0104] Another embodiment of the present invention is a compound ofFormula (I) wherein R¹ is selected from the group consisting of hydrogenand lower alkyl; preferably R¹ is selected from hydrogen or methyl;

[0105] is selected from the group consisting of phenyl, a five to sixmembered heteroaryl and a nine to ten membered benzo-fused heteroaryl;wherein the phenyl, five to six membered heteroaryl or nine to tenmembered benzo-fused heteroaryl is optionally substituted with one totwo substituents independently selected from halogen, lower alkyl, loweralkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy or loweralkoxy-lower alkoxy; preferably

[0106] is selected from the group consisting of phenyl,3,5-dimethoxyphenyl, 4,5-diethoxyphenyl,4,5-di(trifluoromethoxy)-phenyl, 4,5-di(methoxyethoxy)-phenyl,4,5-di(methoxypropoxy)-phenyl, 4,5-di(isopropoxy)-phenyl,4,5-di(difluoromethoxy)-phenyl, 4-chloro-5-methoxy-phenyl,4-methoxyethoxy-5-ethoxy-phenyl, pyridyl, pyrimidinyl, furyl,5-chloro-thienyl, 3-ethoxy-thienyl, isoxazolyl, 3-methyl-isoxazolyl,2-methyl-8-ethoxy-benzoxazolyl, benzothienyl,

[0107] L¹ is absent or selected from lower alkyl, preferably L¹ isabsent or selected from methyl or ethyl;

[0108] is selected from the group consisting of aryl, cycloalkyl and afive to six membered heteroaryl; wherein the aryl or heteroaryl group isoptionally substituted with one to two substituents independentlyselected from halogen, lower alkyl, hydroxy substituted lower alkyl,lower alkoxy, aminosulfonyl, (lower alkyl)amino, di(lower alkyl)amino,di(lower alkyl)amino-alkoxycarbonyl, loweralkoxycarbonyl,heterocycloalkyl-loweralkylaminocarbonyl, di(lower alkyl)amino-loweralkylaminocarbonyl or heteroaryl-loweralkylaminocarbonyl; wherein theheteroaryl or heterocycloalkyl portion of theheterocycloalkyl-loweralkylaminocarbonyl orheteroaryl-loweralkylaminocarbonyl substituent is optionally substitutedwith a substitutent selected from lower alkyl, hydroxy or hydroxysubstituted lower alkyl;

[0109] preferably

[0110] is selected from the group consisting of phenyl, benzyl,phenylethyl, cyclohexyl, cyclohexyl-methyl, 3-hydroxy-cyclohexyl,4-hydroxy-cyclohexyl, 2-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl,2,3-dichlorobenzyl, 2,6-dichlorobenzyl, 2-fluorophenylethyl,3-fluorophenyl, 3-bromophenyl, 3-chlorophenyl, 2-methylbenzyl,3-methylbenzyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-hydroxymethylphenyl,2-hydroxymethyl-benzyl, 3-chloro-4-fluoro-benzyl,2-aminosulfonyl-benzyl, 2-aminosulfonyl-phenyl, 3-aminosulfonyl-phenyl,4-aminosulfonyl-phenyl, 3-dimethylamino-phenyl,3-(dimethylamino-ethylaminocarbonyl)-phenyl, 3-ethoxycarbonyl-phenyl,3-(2-pyrrolidin-1-yl-ethylaminocarbonyl)-phenyl,3-(2-pyrrolidin-1-yl-n-propylaminocabronyl)-phenyl,3-(dimethylamino-ethylaminocarbonyl)-phenyl,3-(2-imidazol-1-yl-ethylaminocarbonyl-phenyl,3-(2-(1-methyl-imidazol-2-yl)-ethylaminocarbonyl)-phenyl,3-[3-(hydroxymethyl-pyrrolidin-1-yl-propyl)-aminocarbonyl]-phenyl,pyridyl-methyl, pyridyl-ethyl, pyrimidinyl-methyl and3-methyl-imidazolyl-methyl;

[0111] or an optical isomer, enantiomer, diastereomer, racemate orpharmaceutically acceptable salt thereof.

[0112] 1 .b. Preparation of Compounds of Formula (I)

[0113] The present invention is further directed to a process for thepreparation of compounds of Formula (I)

[0114] wherein,

[0115] n is an integer from 1 to 4;

[0116] R¹ is selected from the group consisting of hydrogen, loweralkyl, —OH, alkoxy, -oxo, —NH₂, —NH(alkyl) and —N(alkyl)₂;

[0117] is selected from the group consisting of an aryl, a five to sixmembered monocyclic heteroaryl, a nine to ten membered benzo-fusedheteroaryl, a nine to ten membered benzo-fused heterocycloalkyl group,and a nine to ten membered benzo-fused cycloalkyl group; wherein thebenzo-fused heteroaryl, benzo-fused heterocycloalkyl or benzo-fusedcycloalkyl group is attached to the molecule: such that the phenyl ringis bound directly to the

[0118] portion of the molecule;

[0119] p is an integer from 0 to 2;

[0120] R² is selected from the group consisting of

[0121] , and —X-A¹-Y-A²; wherein,

[0122] X and Y are each independently absent or selected from the groupconsisting of —O—, —NH—, —N(alkyl)-, —S—, —SO—, —SO₂—, —OC(═O),—C(═O)O—, —NHC(═O)—, —N(alkyl)C(═O)—, —C(═O)NH—, —C(═O)N(alkyl)-,—OC(═O)O—, —NHC(═O)O—, —OC(═O)NH—, —N(alkyl)C(═O)O—, —OC(═O)N(alkyl)-,—NHC(═O)NH—, —NHC(═O)N(alkyl)—, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)N(alkyl)-, —NHSO₂—, —SO₂NH—, —N(alkyl)SO₂— and—SO₂N(alkyl)-;

[0123] A¹ is absent or selected from alkyl or alkenyl; A² is selectedfrom alkyl, alkenyl, or H; wherein, when A¹ or A² is alkyl or alkenyl,the alkyl or alkenyl group may be optionally substituted with one ormore groups independently selected from halogen, cyano, hydroxy, alkoxy,thio, halogenated alkoxy, —OC(═O)alkyl, —OC(═O)Oalkyl, amino,alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, dialkylamino,—NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)NH₂,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂;

[0124] is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl; wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, is optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, amino, thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy,halogenated alkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, ordialkylamino, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂;

[0125] q is an integer from 0 to 4;

[0126] R³ is selected from the group consisting of halogen, hydroxy,amino, thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy, halogenatedalkyloxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, ordialkylamino, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ and—OC(═O)N(alkyl)₂;

[0127] provided that the sum of p and q is an integer from 0 to 4;

[0128] L¹ is absent or selected from the group consisting of alkyl;

[0129] is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl;

[0130] or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof;

[0131] comprising

[0132] reacting a compound of formula (S1) with1,1′-thiocarbonylimidazole, in the presence of abase, in an aproticsolvent, to yield the corresponding compound of formula (S5);

[0133] reacting the compound of formula (S5) with a compound of formula(S6), in an aprotic solvent, to yield the corresponding compound offormula (S3);

[0134] reacting the compound of formula (S3) with hydrazine, to yieldthe corresponding compound of formula (I).

[0135] 2. Formula (II)

[0136] The present invention is further directed to compounds of Formula(II):

[0137] wherein:

[0138] is selected from the group consisting of Formulae A-1, A-2 andA-3:

[0139] wherein Formula A-1 is attached on the b¹ side of Formula A-1 tothe L² ring of formula (II) and optionally substituted with onesubstituent selected from the group consisting of Formulae A-1-a, A-1-band A-1-c:

[0140] wherein Formula A-1-a is attached on the a¹ side to adjacentcarbons on the d¹or d² side of Formula A-1;

[0141] wherein Formula A-1-b is attached on the a²side to adjacentcarbons on the d¹or d² side of Formula A-1; and

[0142] wherein Formula A-1-c is attached on the a⁶ side to adjacentcarbons on the d¹or d² side of Formula A-1;

[0143] wherein R⁸ is H or alkyl;

[0144] wherein Formula A-2 is attached on the b² side of Formula A-2 tothe L² ring of formula (II), and A¹, A², A³, A⁴are (i) —N—; or (ii) —C—substituted with H or alkoxy, wherein the alkoxy may be optionallyfurther substituted with alkoxy on a terminal carbon or up to 3 halogenatoms on a terminal carbon; provided that at least one and no more thantwo of A¹, A², A³, A⁴ are —N—; and

[0145] wherein Formula A-3 is attached on the b³ side of Formula A-3 tothe L² ring of formula (II), and B¹, B² and B³are independently (i) —CH—optionally substituted with alkyl, aryl, alkoxy, or halogen, (ii) —S—;(iii) —O—; or (iv) —N—; provided that no more than one of B¹, B² or B³is —S— or —O—, and, provided that when one of B¹, B² or B³ is —S— or—O—, then the adjacent ring members are not —S— or —O—;

[0146] R⁹ is independently selected from the group consisting of:alkoxy, alkyl, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkyl, halogenated alkyloxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy, —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —SO₂alkyl, thio and thioalkyl;

[0147] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;wherein R¹⁰⁰ is selected from: alkyl, hydroxy, aryl, alkoxy, oxo, —NH₂,—NH(alkyl) —N(alkyl)₂, ═N(OH) or —NH₂OH; provided that when L² is—CH₂CH₂—, neither R⁶ nor R⁷ is —CH₂—(C═O)NHalkyl, —CH₂—(C═O)N(alkyl)₂ or—CH₂C(═O)Oalkyl; provided that when L² is —OCH(R¹⁰⁰)—, R¹⁰⁰ is alkoxy,and

[0148] is phenyl, R⁵ is not —C(═O)NH—NH₂; and provided that when L² is—O— or —S—, neither R⁶ nor R⁷ is —CH₃;

[0149] R¹⁰ is independently selected from the group consisting of

[0150] and —X¹-A²⁰-Y¹-A²¹;

[0151] wherein X¹ and Y¹ are each independently absent or selected fromthe group consisting of: -(alkyl)C(═O)N(alkyl)-, —C(═O)N(alkyl)-,—C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-,—NHC(═O)NH, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-,—OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)-, and —SO₂NH—;

[0152] A²⁰ is absent or selected from alkyl or alkenyl; and

[0153] A²¹ is selected from alkyl, alkenyl, or H;

[0154] wherein when A²⁰ or A²¹ is alkyl or alkenyl, the alkyl or alkenylmay be optionally substituted with one or more groups independentlyselected from: alkoxy, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkoxy, halogenated —SO₂alkyl, halogenated thioalkyl,hydroxy, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl,—OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio orthioalkyl;

[0155] is selected from the group consisting of aryl, cycloalkyl,partially unsaturated carbocycle, heteroaryl, heterocycloalkyl, nine toten membered benzo-fused cycloalkyl, and nine to ten memberedbenzo-fused heterocycloalkyl; wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, are optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, amino, thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy,halogenated alkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, ordialkylamino, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂;

[0156] s is an integer from 0 to 2;

[0157] m is an integer from 0 to 4; provided that when

[0158] is not substituted with Formulae A-1-a, A-1-b or A-1-c, the sumof m and s is an integer from 0 to 4, and when

[0159] is substituted with one of Formulae A-1-a, A-1-b, or A-1-c, thesum of m and s is an integer from 0 to 2;

[0160] R⁶ and R⁷ are independently selected from the group consistingof:

[0161] (a)

[0162] b)

[0163] provided that R⁴ is not ;

[0164] (c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —(C═O)OH, —C(═O)Oalkyl,—C(═O)Oaryl, —C(═O)Oheteroaryl, —(C═O)NH₂, —(C═O)NHalkyl,—(C═O)N(alkyl)₂, —C(═O)alkyl, -phenyl-OCH₃ or -phenyl-OC(═O)alkyl;

[0165] (d) —C(═O)(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, orbenzyl;

[0166] (e) —C(═O)CH₂O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl,or benzyl;

[0167] (f) —C(═O)alkyl, or —C(═O)(C₃₋₆)cycloalkyl, wherein said—C(═O)alkyl, and —C(═O)(C₃₋₆)cycloalkyl may be optionally substitutedwith one or more groups independently selected from: —OH, —Oalkyl,—Oalkylaryl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl,—NHC(═O)alkyl, —NHSO₂alkyl, or —OC(═O)alkyl;

[0168] (g) —C(═O)(CH₂)₁₋₃aryl, —C(═O)aryl, —C(═O)(CH₂)₁₋₃heteroaryl, or—C(═O)heteroaryl, wherein said —C(═O)(CH₂)₁₋₃aryl, —C(═O)aryl,—C(═O)(CH₂)₁₋₃heteroaryl, and —C(═O)heteroaryl may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl;

[0169] (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with methyl, ethyl, —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, or heterocycloalkyl;

[0170] (hh) —C(═O)alkylOC(═O)alkyl- terminating with —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, or heterocycloalkyl;

[0171] (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, orbenzyl;

[0172] (j) —C(═O)Oalkyl, or —C(═O)O(C₃₋₆)cycloalkyl, wherein said—C(═O)Oalkyl, and —C(═O)O(C₃₋₆)cycloalkyl may be optionally substitutedwith one or more groups independently selected from: —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl,—OC(═O)alkyl, —C(═O)OH, —C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or—C(═O)N(alkyl)₂;

[0173] (k) —C(═O)O(CH₂)₁₋₃aryl, —C(═O)Oaryl, —C(═O)O(CH₂)₁₋₃heteroaryl,or —C(═O)Oheteroaryl, wherein said —C(═O)O(CH₂)₁₋₃aryl, —C(═O)Oaryl,—C(═O)O(CH₂)₁₋₃heteroaryl, or —C(═O)Oheteroaryl may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl;

[0174] (l) —C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H, methyl, ethyl,benzyl, —CH₂CH₂NH₂, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂,—CH₂CH₂-1-pyrrolidinyl, —CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl,—CH₂CH₂-1-piperazinyl, —CH₂CH₂-1-(4-CH₃)-piperazinyl or —C(═O)alkyl;

[0175] (m) —C(═O)NH₂, —C(═O)NH(C₁₋₂₀)alkyl, —C(═O)NH(C₃₋₆)cycloalkyl, or—C(═O)N(alkyl)₂, wherein said —C(═O)NH(C₁₋₂₀)alkyl,—C(═O)NH(C₃₋₆)cycloalkyl, and —C(═O)N(alkyl)₂ may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)alkenyl, —NHC(═O)aryl, —C(═O)OH,—C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂; and, whereinthe aryl portion of said —NHC(═O)aryl may be optionally substituted withone or more groups independently selected from: alkyl, —OH, —Oalkyl,—NH₂, —NHalkyl, —N(alkyl)₂, halogen or nitrile;

[0176] (n) —C(═O)NH(CH₂)₁₋₃aryl, —C(═O)NHaryl,—C(═O)NH(CH₂)₁₋₃heteroaryl, or —C(═O)NHheteroaryl, wherein said—C(═O)NH(CH₂)₁₋₃aryl, —C(═O)NHaryl, —C(═O)NH(CH₂)₁₋₃heteroaryl, and—C(═O)NHheteroaryl may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl;

[0177] (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with H, methyl,ethyl, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃,—CH₂CH₂)C(═O)alkyl, or —C(═O)aryl; wherein the aryl portion of said—C(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile;

[0178] (p) —C(═S)NH₂;

[0179] (q) —C(═S)NHalkyl;

[0180] (r) —C(═S)N(alkyl)₂;

[0181] (s) —SO₂NH₂;

[0182] (t) —SO₂NHalkyl;

[0183] (u) —SO₂N(alkyl)₂;

[0184] (v) —P(═O)(OCH₃)₂; and

[0185] (w) —P(═O)(OCH₂CH₃)₂;

[0186] provided that when R⁶ is present, R⁷ is absent; and provided thatwhen R⁷ is present, R⁶ is absent;

[0187] R⁴ is selected from the group consisting of: H and

[0188] provided that if one of R⁶and R⁷ is

[0189] then R⁴ is H;

[0190] L³ is absent or is a linking group selected from the groupconsisting of alkyidiyl, carbonyl or —SO₂—;

[0191] is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, aralkyl, a heteroaryl, aheterocycloalkyl, a nine to ten membered benzo-fused cycloalkyl, a nineto ten membered benzo-fused heteroaryl, and a nine to ten memberedbenzo-fused heterocycloalkyl;

[0192] r is an integer from 0 to 4; and

[0193] R⁵ is independently selected from the group consisting of: alkyl,alkyl amino, alkyloxy, amino, —C(═O)NH₂, —C(═O)Oalkyl, —C(═O)OH, —CH₂OH,cyano, dialkylamino, halogen, halogenated alkyl, halogenated alkyloxy,halogenated SO₂-alkyl, halogenated thioalkyl, hydroxy, hydroxy alkyl,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —SO₂alkyl,—SO₂NH₂, thio, thioalkyl,

[0194] and —V—B¹⁰—W—B²⁰; wherein,

[0195] V and W are each independently absent or selected from the groupconsisting of: —C(═O), —C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —N(alkyl)-,—N(alkyl)C(═O)—, —N(alkyl)C(═O)N(alkyl)-, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-,—NHC(═O)NH—, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-,—OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂-, -SO₂N(alkyl)- and —SO₂NH—;

[0196] B¹⁰ is absent or selected from alkyl or alkenyl;

[0197] B²⁰ is absent or selected from alkyl, alkenyl, or H;

[0198] wherein, when B¹⁰ or B²⁰ is alkyl or alkenyl, the alkyl oralkenyl group may be optionally substituted with one or more groupsindependently selected from: alkoxy, alkylamino, amino, cyano,dialkylamino, halogen, halogenated alkoxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl; and

[0199] is selected from the group consisting of: an aryl, a cycloalkyl,a partially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl,

[0200] wherein, the aryl, cycloalkyl, partially unsaturated carbocycle,heteroaryl, heterocycloalkyl, benzo-fused cycloalkyl, or benzo-fusedheterocycloalkyl, is optionally substituted with one or moresubstituents independently selected from: alkoxy, alkylamino, amino,cyano, dialkylamino, halogen, halogenated alkoxy, halogenated alkyl,halogenated —SO₂alkyl, halogenated thioalkyl, heteroaryl, hydroxy,hydroxy alkyl, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—SO₂alkyl, thio or thioalkyl;

[0201] or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof.

[0202] In formula (II), “the L² ring of formula (II)” refers to the ringof Formula (II) containing the L² substituent.

[0203] The

[0204] ring of Formula (II) is attached to the L² ring of formula (II)such that the point of attachment for the

[0205] ring is the second and third carbon counterclockwise from thepyrazole nitrogen bearing the R⁶ substituent. For example, where

[0206] L² is —CH₂— and

[0207] is phenyl, the point of attachment is as shown below:

[0208] L² is —CH₂CH₂— and

[0209] is phenyl, the point of attachment is as shown below:

[0210] 2.a Embodiments of Formula (II)

[0211] 2.a.1

[0212] Further emobidments of the present invention include compounds ofFormula II wherein E, L², R⁶, R⁷, R⁴, L³ H, and (R⁵)_(r) vary as setforth below individually and combinations of the variations thereof.

[0213] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0214] is selected from the group consisting of Formulae A-1, A-2 andA-3:

[0215] wherein Formula A-1 is attached on the b¹ side of Formula A-1 tothe L² ring of formulae (II) and optionally substituted with onesubstituent selected from the group consisting of Formulae A-1-a, A-1-band A-1-c:

[0216] wherein Formula A-1-a is attached on the a¹ side to adjacentcarbons on the d¹ or d² side of Formula A-1;

[0217] wherein Formula A-1-b is attached on the a² side to adjacentcarbons on the d¹ or d² side of Formula A-1; and

[0218] wherein Formula A-1-c is attached on the a⁶ side to adjacentcarbons on the d¹ or d² side of Formula A-1;

[0219] wherein R⁸ is H or lower alkyl;

[0220] wherein Formula A-2 is attached on the b² side of Formula A-2 tothe L² ring of formulae (II), and one or two of A¹, A², A³, A⁴ are —N—;the remainder being —C— substituted with H or alkoxy, wherein the alkoxymay be optionally further substituted with alkoxy on a terminal carbonor up to 3 halogen atoms on a terminal carbon; and

[0221] wherein Formula A-3 is attached on the b³ side of Formula A-3 tothe L² ring of formulae (II), and B¹, B² and B³ are independently (i)—CH— optionally substituted with C₁₋₄alkyl, aryl, alkoxy, or halogen,(ii) —S—, (iii) —O— or (iv) —N—; provided that no more than one of B¹,B² or B³ is —S— or —O—, and, provided that when one of B¹, B² or B³ is—S— or —O—, then the adjacent ring members are not —S— or —O—;

[0222] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0223] is selected from the group consisting of Formulae A-1, A-2 andA-3:

[0224] wherein Formula A-1 is attached on the b¹ side of Formula A-1 tothe L² ring of formulae (II) and optionally substituted with onesubstituent selected from the group consisting of Formulae A-1-a, A-1-band A-1-c:

[0225] wherein Formula A-1-a is attached on the a¹ side to adjacentcarbons on the d¹ or d² side of Formula A-1;

[0226] wherein Formula A-1-b is attached on the a² side to adjacentcarbons on the d¹ or d² side of Formula A-1; and

[0227] wherein Formula A-1-c is attached on the a⁶ side to adjacentcarbons on the d¹ or d² side of Formula A-1;

[0228] wherein R⁸ is H or lower alkyl;

[0229] wherein Formula A-2 is selected from the group consisting ofpyridyl and pyrimidinyl; is attached on the b² side of Formula A-2 tothe L² ring of formulae (II); and is optionally substituted on a carbonring member with H or alkoxy, wherein the alkoxy may be optionallyfurther substituted with alkoxy on a terminal carbon or up to 3 halogenatoms on a terminal carbon; and

[0230] wherein Formula A-3 is selected from the group consisting ofthienyl, isoxazolyl and furyl; is attached on the b³ side of Formula A-3to the L² ring of formulae (II), and is optionally substituted on acarbon ring member with C₁₋₄alkyl, aryl, alkoxy, or halogen.

[0231] A embodiment of the present invention includes compounds ofFormula (II) wherein

[0232] is selected from the group consisting of:

[0233] wherein Formula A-4 is attached on the b¹ side of Formula A-4 tothe L² ring of formulae (II);

[0234] wherein Formula A-5 is attached on the b¹ side of Formula A-5 tothe L² ring of Formula (II); wherein R⁸ is H and lower alkyl;

[0235] wherein Formula A-6 is attached on the be side of Formula A-6 tothe L² ring of Formula (II); and

[0236] wherein Formulae A-3-a is attached on the b³ side of FormulaeA-3-a to the L² ring of formula (II), wherein R¹² is independentlyselected from H, methyl, phenyl, ethoxy, chloro or fluoro; and wherein

[0237] m is an integer from 0 to 4; provided that when

[0238] is Formula A-4, the sum of m and s is an integer from 0 to 4, andwhen

[0239] is Formulae A-5 or A-6, the sum of m and s is an integer from 0to 2.

[0240] A embodiment of the present invention includes compounds ofFormula (II) wherein

[0241] is selected from the group consisting of:

[0242] wherein Formula A-4 is attached on the b¹ side of Formula A-4 tothe L² ring of formulae (II);

[0243] wherein Formula A-5 is attached on the b¹ side of Formula A-5 tothe L² ring of Formula (II); wherein R⁸ is H and lower alkyl; and

[0244] wherein Formulae A-3-a is attached on the b³ side of FormulaeA-3-a to the L² ring of formula (II), wherein R¹² is independentlyselected from H, methyl, phenyl, ethoxy, chloro or fluoro; and wherein

[0245] m is an integer from 0 to 4; provided that when

[0246] is Formula A-4, the sum of m and s is an integer from 0 to 4, andwhen

[0247] is Formula A-5, the sum of m and s is an integer from 0 to 2.

[0248] A embodiment of the present invention includes compounds ofFormula (II) wherein

[0249] is:

[0250] wherein Formula A-4 is attached on the b¹ side of Formula A-4 tothe L² ring of formulae (II); and wherein

[0251] m is an integer from 0 to 4; provided that when

[0252] is Formula A-4, the sum of m and s is an integer from 0 to 4.

[0253] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0254] R⁹ is independently selected from the group consisting of:alkoxy, alkyl, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkyl, halogenated alkyloxy, halogenated thioalkyl, hydroxy,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl and thioalkyl.

[0255] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0256] R⁹ is independently selected from the group consisting of:alkoxy, alkyl, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkyl, halogenated alkyloxy, hydroxy, —NHC(═O)alkyl,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, and thioalkyl.

[0257] A embodiment of the present invention includes compounds ofFormula (II) wherein:

[0258] R⁹ is independently selected from the group consisting of:alkoxy, alkyl, amino, cyano, dialkylamino, halogen, halogenated alkyl,halogenated alkyloxy, hydroxy and —NHC(═O)alkyl.

[0259] A embodiment of the present invention includes compounds ofFormula (II) wherein:

[0260] R⁹ is independently selected from the group consisting of:methoxy, ethoxy, isopropoxy, methyl, amino, cyano, N,N-dimethyl-amino,bromo, chloro, fluoro, trifluoromethyl, trifluoromethoxy, hydroxy andN-(1-oxo-ethyl)-amino.

[0261] An embodiment of the present invention includes compounds ofFormulae (II) wherein:

[0262] L² is a linking group selected from the group consisting of:—(CH₂)—, —(CH₂)₃₋₄—, —CH(R¹⁰⁰)—, —C(+R¹⁰⁰)—, —C(R¹⁰⁰)₂-, —O—,—O(CH₂)₁₋₄—, —OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-,—N(COalkyl)-, —N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and—N(SO₂aryl)-.

[0263] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0264] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—,—OCH(R²⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;wherein R²⁰⁰ is selected from: alkyl, hydroxy, aryl, oxo, —NH₂,—NH(alkyl) —N(alkyl)₂; ═N(OH) or —NH₂OH.

[0265] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0266] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-.

[0267] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0268] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-.

[0269] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0270] L² is a linking group selected from the group consisting of:—(CH₂)—, —(CH₂)₃₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O(CH₂)₁₋₄—,—OCH(R²⁰⁰)—, —OC(R¹⁰⁰)₂—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;wherein R²⁰⁰ is selected from: alkyl, hydroxy, aryl, oxo, —NH₂,—NH(alkyl) —N(alkyl)₂, ═N(OH) or —NH₂OH.

[0271] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0272] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)₂—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;provided that when L² is —CH₂CH₂—, neither R⁶ nor R⁷ is—CH₂—(C═O)NHalkyl.

[0273] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0274] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;provided that when L² is —CH₂CH₂—, neither R⁶ nor R⁷ is—CH₂—(C═O)NHalkyl or —CH₂—(C═O)N(alkyl)₂.

[0275] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0276] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂-, —O—, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;provided that when L² is —CH₂CH₂—, neither R⁶ nor R⁷ is —CH₂C(═O)Oalkyl.

[0277] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0278] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;provided that when L² is —CH₂CH₂—, neither R⁶ nor R⁷ is—CH₂—(C═O)NHalkyl, —CH₂—(C═O)N(alkyl)₂ or —CH₂C(═O)Oalkyl.

[0279] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0280] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;provided that when L² is —OCH(R¹⁰⁰)—, R¹⁰⁰ is alkoxy, and

[0281] is phenyl, R⁵ is not —C(═O)NH—NH₂.

[0282] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0283] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;provided that when L² is —O—, neither R⁶ nor R⁷ is —CH₃.

[0284] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0285] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;provided that when L² is —S—, neither R⁶ nor R⁷ is —CH₃.

[0286] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0287] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—,—OC(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;provided that when L² is —O— or —S—, neither R⁶ nor R⁷ is —CH₃.

[0288] A embodiment of the present invention includes compounds ofFormula (II) wherein:

[0289] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁾⁾)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—,—N(COalkyl)-, —N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and—N(SO₂aryl)-.

[0290] A embodiment of the present invention includes compounds ofFormula (II) wherein:

[0291] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂- , —O—, and —O(CH₂)₁₋₄—.

[0292] A embodiment of the present invention includes compounds ofFormula (II), wherein:

[0293] R¹⁰⁰ is selected from: alkyl, hydroxy, aryl, oxo or ═N(OH).

[0294] A embodiment of the present invention includes compounds ofFormula (II) wherein:

[0295] R¹⁰⁰ is selected from: alkyl, hydroxy, aryl, or oxo.

[0296] An embodiment of the present invention includes compounds ofFormulae (II) wherein:

[0297] R¹⁰⁰ is selected from: methyl, hydroxy, phenyl, oxo or ═N(OH).

[0298] A embodiment of the present invention includes compounds ofFormulae (II) wherein:

[0299] R¹⁰⁰ is selected from: methyl, hydroxy, phenyl, or oxo.

[0300] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0301] R¹⁰ is independently selected from the group consisting of

[0302]13 X¹-A²⁰-Y¹-A²¹, —X¹-A²⁰-A²¹, —X¹-A²¹, -A²⁰-A²¹ and -A²¹.

[0303] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0304] R¹⁰ is independently selected from the group consisting of

[0305] —X¹-A²⁰-Y¹A²¹, —X¹-A²⁰-A²¹ and —X¹-A²¹.

[0306] An embodiment of the present invention includes compounds ofFormula (II):

[0307] wherein X¹ and Y¹ are each independently absent or selected fromthe group consisting of: —C(═O)NH—, —C(═O)O—, —NH—, —NHC(═O)—,—NHC(═O)NH, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)NH—, —OC(═O)O—,—S—, —SO—, —SO₂— and —SO₂NH—.

[0308] An embodiment of the present invention includes compounds ofFormula (II):

[0309] wherein X¹ and Y¹ are each independently absent or selected fromthe group consisting of: —NH—, —O—, —SO₂— and —SO₂NH—.

[0310] An embodiment of the present invention includes compounds ofFormula (II), wherein X¹ and Y¹ are each independently absent or —O—.

[0311] An embodiment of the present invention includes compounds ofFormula (II), wherein X¹ is absent or —O—.

[0312] An embodiment of the present invention includes compounds ofFormula (II), wherein Y¹ is absent.

[0313] An embodiment of the present invention includes compounds ofFormula (II), wherein:

[0314] A²⁰ is absent or alkyl; and

[0315] wherein when A²⁰ is alkyl, the alkyl may be optionallysubstituted with one or more groups independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated —SO₂alkyl, halogenated thioalkyl, hydroxy,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl.

[0316] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0317] A²⁰ is absent or alkyl; and

[0318] wherein when A²⁰ is alkyl, the alkyl may be optionallysubstituted with one or more groups independently selected from: alkoxy,alkylamino, amino, dialkylamino, halogen, halogenated alkoxy, hydroxy,—NHC(═O)NH₂, —NHSO₂alkyl, —SO₂alkyl orthioalkyl.

[0319] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0320] A²⁰ is absent or selected from methyl, ethyl, propyl orisopropyl; wherein methyl, ethyl, propyl or isopropyl are optionallysubstituted with one or more groups independently selected from: alkoxy,dialkylamino or hydroxy.

[0321] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0322] A²⁰ is absent or selected from methyl, ethyl, propyl orisopropyl; wherein methyl, ethyl, propyl or isopropyl are optionallysubstituted with one or more groups independently selected from methoxy,dimethyl-amino or hydroxy.

[0323] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0324] A²¹ is selected from alkyl, alkenyl, or H; and

[0325] wherein when A²¹ is alkyl or alkenyl, the alkyl or alkenyl may beoptionally substituted with one or more groups independently selectedfrom:

[0326] alkoxy, alkylamino, amino, cyanob,dialkylamino, halogen,halogenated alkoxy, halogenated —SO₂alkyl, halogenated thioalkyl,hydroxy, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl,—OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio orthioalkyl.

[0327] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0328] A²¹ is selected from alkyl, alkenyl, or H; and

[0329] wherein when A²¹ is alkyl or alkenyl, the alkyl or alkenyl may beoptionally substituted with one or more groups independently selectedfrom:

[0330] alkoxy, alkylamino, amino, dialkylamino, halogen, halogenatedalkoxy, hydroxy, —NHC(═O)NH₂, —NHSO₂alkyl or thioalkyl.

[0331] An embodiment of the present invention includes compounds ofFormula (II) wherein A²¹ is H.

[0332] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0333] is selected from the group consisting of aryl, cycloalkyl,partially unsaturated carbocycle, heteroaryl and heterocycloalkyloptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, amino, thio, nitro, cyano, alkyl,halogenated alkyl, alkoxy, halogenated alkoxy, alkylamino,—NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, or dialkylamino, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —OC(═O)NHalkyl, —NHC(═O)Oalkyl,—N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl, —N(alkyl)SO₂alkyl, thioalkyl,halogenated thioalkyl, —SO₂alkyl, halogenated —SO₂alkyl,—NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or —OC(═O)N(alkyl)₂.

[0334] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0335] is selected from the group consisting of aryl, heteroaryl andheterocycloalkyl optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, amino, thio, nitro, cyano,alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, alkylamino,—NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, or dialkylamino, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —OC(═O)NHalkyl, —NHC(═O)Oalkyl,—N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl, —N(alkyl)SO₂alkyl, thioalkyl,halogenated thioalkyl, —SO₂alkyl, halogenated —SO₂alkyl,—NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or —OC(═O)N(alkyl)₂.

[0336] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0337] is selected from the group consisting of phenyl, imidazolyl,pyrrolidinyl, piperidinyl and morpholinyl optionally substituted withone or more substituents independently selected from halogen, hydroxy,amino, thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy, halogenatedalkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, or dialkylamino,—NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —OC(═O)NHalkyl,—NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl, —N(alkyl)SO₂alkyl,thioalkyl, halogenated thioalkyl, —SO₂alkyl, halogenated —SO₂alkyl,—NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or —OC(═O)N(alkyl)₂.

[0338] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0339] is selected from the group consisting of phenyl, imidazolyl,pyrrolidinyl, piperidinyl and morpholinyl optionally substituted withone or more substituents independently selected from halogen, hydroxy,amino, nitro, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy,alkylamino, dialkylamino, —NHSO₂alkyl or —SO₂alkyl.

[0340] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0341] is selected from the group consisting of phenyl, imidazolyl,pyrrolidinyl, piperidinyl and morpholinyl optionally substituted withone or more substituents independently selected from chloro, fluoro,hydroxy or alkyl.

[0342] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0343] R⁹ and R¹⁰ are independently selected from the group consistingof: 1-piperidinyl, 2-(pyrrolidin-1-yl)-ethoxy, 2,3-dihydroxy-propoxy,2-hydroxy- 3-pyrrolidin-1-yl-propoxy,3-(4-methyl-piperazin-1-yl)-propoxy, 3-(N,N-dimethyl-amino)-propoxy,3-hydroxy-propoxy, 3-imidazol-1-yl-propoxy, 3-methoxy-propoxy,3-morpholin-4-yl-propoxy, 3-pyrrolidin-1-yl-2- hydroxy-propoxy,3-pyrrolidin-1-yl-propoxy, 4-methyl-piperazin-1-yl, amino, benzyl,benzyloxy, bromo, chloro, cyano, ethoxy, fluoro, H, hydroxy, isopropoxy,methoxy, methyl, N-(1-oxo-ethyl)-amino, and N,N-dimethyl-amino.

[0344] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0345] R⁶ and R⁷ are independently selected from the group consistingof:

[0346] (a) H;

[0347] (b)

[0348] provided that R⁴ is not

[0349] (c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —(C═O)OH, —C(═O)Oalkyl,—C(═O)Oaryl, —C(═O)Oheteroaryl, —(C═O)NH₂, —(C═O)NHalkyl,—(C═O)N(alkyl)₂, —C(═O)alkyl, -phenyl-OCH₃ or -phenyl-OC(═O)alkyl;

[0350] (d) —C(═O)(CH₂CH₂)₁₋₁₀ terminating with H;

[0351] (e) —C(═O)CH₂O(CH₂CH₂O—)₁₋₁₀ terminating with H;

[0352] (f) —C(═O)alkyl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —Oalkylaryl, —NH₂, —NHalkyl,—N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, or—OC(═O)alkyl;

[0353] (g) —C(═O)(CH₂)₁₋₃aryl or —C(═O)aryl, wherein said —C(═O)aryl maybe optionally substituted with one or more groups independently selectedfrom: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl,—NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl;

[0354] (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with methyl, ethyl, —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, or heterocycloalkyl;

[0355] (hh) —C(═O)alkylOC(═O)alkyl- terminating with —OH, —Oalkyl, —NH₂,—NHalkyl or —N(alkyl)₂;

[0356] (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, orbenzyl;

[0357] (j) —C(═O)Oalkyloptionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, —OC(═O)alkyl, —C(═O)OH,—C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂;

[0358] (k) —C(═O)O(CH₂)₁₋₃aryl or —C(═O)Oaryl, wherein said —C(═O)Oarylmay be optionally substituted with one or more groups independentlyselected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile,or—OC(═O)alkyl;

[0359] (l) —C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H, methyl, ethyl,benzyl,—CH₂CH₂NH₂, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl, —CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl,—CH₂CH₂-1-piperazinyl, —CH₂CH₂-1-(4-CH₃)-piperazinyl or —C(═O)alkyl;

[0360] (m) —C(═O)NH₂, —C(═O)NH(C₁₋₂₀)alkyl, or —C(═O)N(C₁₋₂₀alkyl)₂,wherein said —C(═O)NH(C₁₋₂₀)alkyl, may be optionally substituted withone or more groups independently selected from: —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl,—OC(═O)alkyl, —OC(═O)alkenyl, —NHC(═O)aryl, —C(═O)OH, —C(═O)Oalkyl,—C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂; and, wherein the arylportion of said —NHC(═O)aryl may be optionally substituted with one ormore groups independently selected from: alkyl, —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, halogen or nitrile;

[0361] (n) —C(═O)NH(CH₂)₁₋₃aryl or —C(═O)NHaryl, wherein said—C(═O)NHaryl may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl;

[0362] (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with H, methyl,ethyl, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃,—CH₂CH₂OC(═O)alkyl or —C(═O)aryl; wherein the aryl portion of said—C(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH , —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile;

[0363] (p) —C(═S)NH₂;

[0364] (q) —C(═S)NHalkyl;

[0365] (r) —C(═S)N(alkyl)₂;

[0366] (s) —SO₂NH₂;

[0367] (t) —SO₂NHalkyl;

[0368] (u) —SO₂N(alkyl)₂;

[0369] (v) —P(═O)(OCH₃)₂; and

[0370] (w) —P(═O)(OCH₂CH₃)₂;

[0371] provided that when R⁶ is present, R⁷ is absent; and provided thatwhen R⁷ is present, R⁶ is absent.

[0372] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0373] R6 and R⁷ are independently selected from the group consistingof:

[0374] (a) H;

[0375] (b)

[0376] provided that R⁴ is not

[0377] (c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —(C═O)OH, —C(═O)Oalkyl,—C(═O)Oaryl, —C(═O)Oheteroaryl, —(C═O)NH₂, —(C═O)NHalkyl,—(C═O)N(alkyl)₂, —C(═O)alkyl, -phenyl—OCH₃ or -phenyl-OC(═O)alkyl;

[0378] (f) —C(═O)alkyl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —Oalkylaryl, —NH₂, —NHalkyl,—N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, or—OC(═O)alkyl;

[0379] (g) —C(═O)(CH₂)₁₋₃aryl or —C(═O)aryl, wherein said —C(═O)aryl maybe optionally substituted with one or more groups independently selectedfrom: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl,—NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl;

[0380] (h) —C(═O)(CH₂)₁—CC(═O)— terminating with methyl, ethyl, —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, or heterocycloalkyl;

[0381] (hh) —C(═O)alkylOC(═O)alkyl— terminating with —OH, —Oalkyl, —NH₂,—NHalkyl or —N(alkyl)₂;

[0382] (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, orbenzyl;

[0383] (j) —C(═O)Oalkyloptionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, —OC(═O)alkyl, —C(═O)OH,—C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂;

[0384] (k) —C(═O)O(CH₂)₁₋₃aryl or —C(═O)Oaryl, wherein said —C(═O)Oarylmay be optionally substituted with one or more groups independentlyselected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl;

[0385] (l) —C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H, methyl, ethyl,benzyl,—CH₂CH₂NH₂, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂,—CH₂CH₂-1-pyrrolidinyl, —CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl,—CH₂CH₂-1-piperazinyl, —CH₂CH₂-1-(4-CH₃)-piperazinyl or —C(═O)alkyl;

[0386] (m) —C(═O)NH₂, —C(═O)NH(C₁₋₂₀)alkyl, or —C(═O)N(C₁₋₂₀alkyl)₂,wherein said —C(═O)NH(C₁₋₂₀)alkyl, may be optionally substituted withone or more groups independently selected from: —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl,—OC(═O)alkyl, —OC(═O)alkenyl, —NHC(═O)aryl, —C(═O)OH, —C(═O)Oalkyl,—C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂; and, wherein the arylportion of said —NHC(═O)aryl may be optionally substituted with one ormore groups independently selected from: alkyl, —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, halogen or nitrile;

[0387] (n) —C(═O)NH(CH₂)₁₋₃aryl or —C(═O)NHaryl, wherein said—C(═O)NHaryl may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl;

[0388] (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with H, methyl,ethyl, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4—CH₃)-piperazinyl, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃,—CH₂CH₂OC(═O)alkyl, or —C(═O)aryl; wherein the aryl portion of said—C(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH , —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile;

[0389] (p) —C(═S)NH₂;

[0390] (u) —SO₂N(alkyl)₂; and

[0391] (w) —P(═O)(OCH₂CH₃)₂;

[0392] provided that when R⁶ is present, R⁷ is absent; and provided thatwhen R⁷ is present, R⁶ is absent.

[0393] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0394] R⁶ and R⁷ are independently selected from the group consistingof:

[0395] (a)

[0396] (b)

[0397] provided that R⁴ is not

[0398] (c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —(C═O)OH, —C(═O)Oalkyl,—C(═O)Oaryl, —C(═O)Oheteroaryl, —(C═O)NH₂, —(C═O)NHalkyl,—(C═O)N(alkyl)₂, —C(═O)alkyl, -phenyl-OCH₃ or -phenyl-OC(═O)alkyl;

[0399] (f) —C(═O)alkyl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —Oalkylaryl, —NH₂, —NHalkyl,—N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, or—OC(═O)alkyl;

[0400] (g) —C(═O)aryl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl;

[0401] (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with methyl, ethyl, —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, or heterocycloalkyl;

[0402] (hh) —C(═O)alkylOC(═O)alkyl-terminating with —OH, —Oalkyl, —NH₂,—NHalkyl or —N(alkyl)₂;

[0403] (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, orbenzyl;

[0404] (j) —C(═O)Oalkyloptionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, —OC(═O)alkyl, —C(═O)OH,—C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂;

[0405] (k) —C(═O)Oaryl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl;

[0406] (l) —C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H, methyl, ethyl,benzyl, —CH₂CH₂NH₂, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂,—CH₂CH₂-1-pyrrolidinyl, —CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl,—CH₂CH₂-1-piperazinyl, —CH₂CH₂-1-(4-CH₃)-piperazinyl or —C(═O)alkyl;

[0407] (m) —C(═O)NH(C₁₋₂₀)alkyl optionally substituted with one or moregroups independently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, —OC(═O)alkyl,—OC(═O)alkenyl, —NHC(═O)aryl, —C(═O)OH, —C(═O)Oalkyl, —C(═O)NH₂,—C(═O)NHalkyl, or —C(═O)N(alkyl)₂; and, wherein the aryl portion of said—NHC(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile;

[0408] (n) —C(═O)NHaryl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl;

[0409] (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with H, methyl,ethyl, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃,—CH₂CH₂OC(═O)alkyl, or —C(═O)aryl; wherein the aryl portion of said—C(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile;

[0410] (p) —C(═S)NH₂;

[0411] (u) —SO₂N(alkyl)₂; and

[0412] (w) —P(═O)(OCH₂CH₃)₂;

[0413] provided that when R⁶ is present, R⁷ is absent; and provided thatwhen R⁷ is present, R⁶ is absent.

[0414] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0415] R⁶ and R⁷ are independently selected from the group consistingof:

[0416] (a)

[0417] (b)

[0418] provided that R⁴ is not

[0419] (c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —(C═O)OH, —C(═O)Oalkyl,—C(═O)Oaryl, —C(═O)Oheteroaryl, —(C═O)NH₂, —(C═O)NHalkyl,—(C═O)N(alkyl)₂, —C(═O)alkyl, -phenyl-OCH₃ or -phenyl-OC(═O)alkyl;

[0420] (f) —C(═O)alkyl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —Oalkyl-phenyl, —NH₂,—NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, or—OC(═O)alkyl;

[0421] (g) —C(═O)aryl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, chloro, fluoro, nitrile,or —OC(═O)alkyl;

[0422] (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with methyl, ethyl, —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, or pyrrolidinyl;

[0423] (hh) —C(═O)alkylOC(═O)alkyl-terminating with —OH, —Oalkyl, —NH₂,—NHalkyl or —N(alkyl)₂;

[0424] (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, orbenzyl;

[0425] (j) —C(═O)Oalkyloptionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, —OC(═O)alkyl, —C(═O)OH,—C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂;

[0426] (k) —C(═O)Oaryl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, chloro, fluoro, nitrile,or —OC(═O)alkyl;

[0427] (l) —C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H, methyl, ethyl,benzyl, —CH₂CH₂NH₂, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂,—CH₂CH₂-1-pyrrolidinyl, —CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl,—CH₂CH₂-1-piperazinyl, —CH₂CH₂-1-(4-CH₃)-piperazinyl or —C(═O)alkyl;

[0428] (m) —C(═O)NH(C₁₋₂₀)alkyl optionally substituted with one or moregroups independently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, pyrrolidinyl, morpholinyl, —NHC(═O)alkyl, —NHSO₂alkyl,—OC(═O)alkyl, —OC(═O)alkenyl, —NHC(═O)phenyl, —C(═O)OH, —C(═O)Oalkyl,—C(═O)NH₂, —C(═O)NHalkyl, or —C(=O)N(alkyl)₂; and, wherein the phenylportion of said —NHC(═O)phenyl may be optionally substituted with one ormore groups independently selected from: alkyl, —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, halogen or nitrile;

[0429] (n) —C(═O)NHaryl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, chloro, fluoro, nitrile,or —OC(═O)alkyl;

[0430] (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with H, methyl,ethyl, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃,—CH₂CH₂OC(═O)alkyl, or —C(═O)phenyl; wherein the phenyl portion of said—C(═O)phenyl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile;

[0431] (p) —C(═S)NH₂;

[0432] (u) —SO₂N(alkyl)₂; and

[0433] (w) —P(═O)(OCH₂CH₃)₂;

[0434] provided that when R⁶ is present, R⁷ is absent; and provided thatwhen R⁷ is present, R⁶ is absent.

[0435] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0436] R⁶ and R⁷ are independently selected from the group consistingof:

[0437] (a)

[0438] (b)

[0439] provided that R⁴ is not

[0440] (c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —C(═O)Oalkyl, —(C═O)NH₂,—C(═O)alkyl or -phenyl-OC(═O)alkyl;

[0441] (f) —C(═O)alkyl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —Oalkyl-phenyl or—OC(═O)alkyl;

[0442] (g) —C(═O)phenyl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, chloro, fluoro, nitrile,or —OC(═O)alkyl;

[0443] (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, or pyrrolidinyl;

[0444] (hh) —C(═O)alkylOC(═O)alkyl-terminating with —Oalkyl;

[0445] (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminating with H or benzyl;

[0446] (j) —C(═O)Oalkyloptionally substituted with one or more —Oalkylgroups;

[0447] (k) —C(═O)Ophenyl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, chloro, fluoro, nitrile,or —OC(═O)alkyl;

[0448] (l) —C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H;

[0449] (m) —C(═O)NH(C₁₋₂₀)alkyl optionally substituted with one or moregroups independently selected from: —NH₂, —NHalkyl, —N(alkyl)₂,pyrrolidinyl, morpholinyl, —NHC(═O)alkyl, —OC(═O)alkenyl, —NHC(═O)phenylor —C(═O)Oalkyl; and, wherein the phenyl portion of said —NHC(═O)phenylmay be optionally substituted with one or more groups independentlyselected from: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, halogenor nitrile;

[0450] (n) —C(═O)NHphenyl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, chloro, fluoro, nitrile,or —OC(═O)alkyl;

[0451] (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with H, methyl,ethyl, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃,—CH₂CH₂OC(═O)alkyl, and —C(═O)phenyl; wherein the phenyl portion of said—C(═O)phenyl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen and nitrile;

[0452] (p) —C(═S)NH₂;

[0453] (u) —SO₂N(alkyl)₂; and

[0454] (w) —P(═O)(OCH₂CH₃)₂;

[0455] provided that when R⁶ is present, R⁷ is absent; and provided thatwhen R⁷ is present, R⁶ is absent.

[0456] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0457] R⁶ and R⁷ are independently selected from the group consistingof:

[0458] (a)

[0459] (b)

[0460] provided that R⁴ is not

[0461] (c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —C(═O)Oalkyl, —(C═O)NH₂,—C(═O)alkyl or -phenyl-OC(═O)alkyl;

[0462] (f) —C(═O)alkyl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —Oalkyl-phenyl or—OC(═O)alkyl;

[0463] (g) —C(═O)phenyl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, chloro, fluoro, nitrile,and-OC(═O)alkyl;

[0464] (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with —OH, —Oalkyl, —NH₂,-NHalkyl, —N(alkyl)₂, or pyrrolidinyl;

[0465] (hh) —C(═O)alkylOC(═O)alkyl-terminating with —Oalkyl;

[0466] (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminating with H or benzyl;

[0467] (j) —C(═O)Oalkyloptionally substituted with one or more —Oalkylgroups;

[0468] (k) —C(═O)Ophenyl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, chloro, fluoro, nitrile,and —OC(═O)alkyl;

[0469] (l) —C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H;

[0470] (m) —C(═O)NH(C₁₋₂₀)alkyl optionally substituted with one or moregroups independently selected from: —NH₂, —NHalkyl, —N(alkyl)₂,pyrrolidinyl, morpholinyl, —NHC(═O)alkyl, —OC(═O)alkenyl, —NHC(═O)phenylor —C(═O)Oalkyl; and, wherein the phenyl portion of said —NHC(═O)phenylmay be optionally substituted with one or more groups independentlyselected from: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, halogenand nitrile;

[0471] (n) —C(═O)NHphenyl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, chloro, fluoro, nitrile,and —OC(═O)alkyl;

[0472] (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with —CH₂CH₂OH and—C(═O)phenyl; wherein the phenyl portion of said —C(═O)phenyl may beoptionally substituted with one or more groups independently selectedfrom: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, halogen andnitrile;

[0473] (p) —C(═S)NH₂;

[0474] (u) —SO₂N(alkyl)₂; and

[0475] (w) —P(═O)(OCH₂CH₃)₂;

[0476] provided that when R⁶ is present, R⁷ is absent; and provided thatwhen R⁷ is present, R⁶ is absent.

[0477] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0478] R⁶ and R⁷ are independently selected from the group consistingof:

[0479] (a) H;

[0480] (b)

[0481] provided that R⁴ is not

[0482] (c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —C(═O)Oalkyl, —(C═O)NH₂,—C(═O)alkyl or -phenyl-OC(═O)alkyl;

[0483] (f) —C(═O)alkyl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —Oalkyl-phenyl or—OC(═O)alkyl;

[0484] (g) —C(═O)phenyl optionally substituted with one or more groupsindependently selected from: —Oalkyl, chloro or fluoro,;

[0485] (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, or pyrrolidinyl;

[0486] (hh) —C(═O)alkylOC(═O)alkyl-terminating with —Oalkyl;

[0487] (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminating with H or benzyl;

[0488] (j) —C(═O)Oalkyloptionally substituted with one or more —Oalkylgroups;

[0489] (k) —C(═O)Ophenyl optionally substituted with one or more chloro,fluoro groups;

[0490] (l) —C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H;

[0491] (m) —C(═O)NH(C₁₋₂₀)alkyl optionally substituted with one or moregroups independently selected from: —NH₂, —NHalkyl, —N(alkyl)₂,pyrrolidinyl, morpholinyl, —NHC(═O)alkyl, —OC(═O)alkenyl, —NHC(═O)phenylor —C(═O)Oalkyl; and, wherein the phenyl portion of said —NHC(═O)phenylmay be optionally substituted with one or more groups independentlyselected from: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, halogenand nitrile;

[0492] (n) —C(═O)NHphenyl optionally substituted with one or more fluorogroups;

[0493] (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with —CH₂CH₂OH and—C(═O)phenyl; wherein the phenyl portion of said —C(═O)phenyl may beoptionally substituted with one or more —OHgroups;

[0494] (p) —C(═S)NH₂;

[0495] (u) —SO₂N(alkyl)₂; and

[0496] (w) —P(═O)(OCH₂CH₃)₂;

[0497] provided that when R⁶ is present, R⁷ is absent; and provided thatwhen R⁷ is present, R⁶ is absent.

[0498] An embodiment of the present invention includes compounds ofFormulae (II) wherein

[0499] R⁶ and R⁷ are independently selected from the group consistingof: H,

[0500] provided that R⁴ is not

[0501] 1-methoxy-1-oxo-ethyl, 1-methyl-ethoxy-carbonyl,1-oxo-butoxy-methyl,

[0502] 1-oxo-ethoxy-methyl, 1-oxo-ethyl, 1-oxo-propyl,

[0503] 2-(1-oxo-ethoxy)-1-oxo-ethyl,2-(2-methoxy-1-oxo-ethoxy)-1-oxo-ethyl,

[0504] 2-(2-methyl-1-oxo-propoxy)-1-oxo-ethyl, 2-amino-2-oxo-ethyl,

[0505] 2,2-dimethyl-1-oxo-propoxy-methyl, 2-ethoxy2-oxo-ethyl,

[0506] 2-methoxy-2-oxo-ethyl, 2,6-difluoro-benzoyl,

[0507] 2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy-carbonyl,

[0508] 2-benzyloxy-1-oxo-ethyl, 2-benzyloxy-ethoxy-carbonyl,

[0509] 2-chloro-phenoxy-carbonyl, 2-fluoro-benzoyl,2-hydroxy-1-oxo-ethyl,

[0510] 2-hydroxy-ethyl, 2-hydroxy-propyl, 2-methoxy-1-oxo-ethyl,

[0511] 2-methoxy-ethoxy-carbonyl, 2-methyl-1-oxo-propyl, 2-oxo-propyl,

[0512] 3-(N,N-diethyl amino)-1,3-dioxo-propyl,

[0513] 3-1H-pyrrolidin-1-yl-1,3-dioxo-propyl, 3-ethoxy-1,3-dioxo-propyl,

[0514] 3-1H-pyrrolidin-1-yl-1,3-dioxo-propyl, 4-(1-oxo-ethoxy)-benzyl,

[0515] 4-amino-1,4-dioxo-n-butyl, 4-ethoxy-1,4-dioxo-n-butyl,

[0516] 4-hydroxy-1,4-dioxo-n-butyl, 4-methoxy-1,4-dioxo-n-butyl,

[0517] 4-chloro-benzoyl, 4-chloro-phenoxy-carbonyl, 4-fluoro-benzoyl,

[0518] 4-fluoro-phenoxy-carbonyl, 4-methoxy-benzoyl,

[0519] 5-(N-methyl-amino)-1,5-dioxo-pentyl, 5-methoxy-1,5-dioxo-pentyl,benzoyl, diethoxy-phosphinyl, ethoxy-carbonyl, methoxy-carbonyl,methoxy-methyl, methyl, N-(2-ethoxy-2-oxo-ethyl)-amino-carbonyl,

[0520] N-(2-1H-pyrrolidin-1-yl-ethyl)-amino-carbonyl,

[0521] N-(2-amino-ethyl)-amino-carbonyl,

[0522] N-(2-morpholin-4-yl-ethyl)-amino-carbonyl,

[0523] N-(3-ethoxy-3-oxo-propyl)-amino-carbonyl,

[0524] N-(3-fluoro-phenyl)-amino-carbonyl,N-(pentadecyl)-amino-carbonyl,

[0525] N,N-dimethyl-amino-sulfonyl,

[0526] N-[2-(2-methenyl-1-oxo-propoxy)-ethyl]-amino-carbonyl,

[0527] N-[2-(3-methyl-1-methoxy-1-oxo)-n-butyl]-amino-carbonyl,

[0528] N-[2-(4-methyl-1-methoxy-1-oxo)-pentyl]-amino-carbonyl,

[0529] N-[2-(N,N-dimethyl-amino)-ethyl]-amino-carbonyl,

[0530] N-[2-(N-benzoyl-amino)-ethyl]-amino-carbonyl,

[0531] N-[2-(N-methyl-amino)-ethyl]-amino-carbonyl,

[0532] N-[2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethyl]-amino-carbonyl,

[0533] N-[2-[N-(1-oxo-ethyl)-amino]-ethyl]-amino-carbonyl,

[0534] N-[2-[N-(2-hydroxy-benzoyl)-amino]-ethyl]-amino-carbonyl,

[0535] N-[2-[N-(2-hydroxy-ethyl)-amino]-ethyl]-amino-carbonyl,

[0536] N-[2-[N-(2-methyl-1-oxo-propyl)-amino]-ethyl]-amino-carbonyl,

[0537] N-methyl-amino-carbonyl, N-methyl-amino-thiocarbonyl, and

[0538] phenoxy-carbonyl, provided that when R⁶ is present, R⁷ is absent;and

[0539] provided that when R⁷ is present, R⁶ is absent.

[0540] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0541] L³ is absent or is a linking group selected from the groupconsisting of

[0542] methylene, ethylene, carbonyl or —SO₂—.

[0543] A embodiment of the present invention includes compounds ofFormula (II) wherein

[0544] L³ is absent or is a linking group selected from the groupconsisting of

[0545] methylene, ethylene or carbonyl.

[0546] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0547] is selected from the group consisting of an aryl, a cycloalkyl, aheteroaryl, a heterocycloalkyl, a nine to ten membered benzo-fusedcycloalkyl, a nine to ten membered benzo-fused heteroaryl, and a nine toten membered benzo-fused heterocycloalkyl.

[0548] A embodiment of the present invention includes compounds ofFormula (II) wherein

[0549] is selected from the group consisting of an aryl, a cycloalkyl, aheteroaryl, a heterocycloalkyl, a nine to ten membered benzo-fusedcycloalkyl and a nine to ten membered benzo-fused heterocycloalkyl.

[0550] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0551] is selected from the group consisting of phenyl, cyclohexyl,furyl, imidazolyl, isoxazolyl, pyridyl, pyrimidinyl, indolyl, indazolyl,piperidinyl, morpholinyl, indanyl, 2,3-dihydro-1H-indolyl andbenzodioxolyl.

[0552] A embodiment of the present invention includes compounds ofFormula (II) wherein

[0553] R⁵ is independently selected from the group consisting of: alkyl,alkyloxy, amino, —C(═O)NH₂, —C(═O)Oalkyl, —C(═O)OH, cyano, dialkylamino,halogen, halogenated alkyl, halogenated alkyloxy, halogenated thioalkyl,hydroxy, hydroxy alkyl, —NHC(═O)NH₂, —NHSQ₂alkyl, nitro, —SO₂alkyl,—SO₂NH₂, thio, thioalkyl,

[0554] and —V—B¹⁰—W—B²⁰.

[0555] A embodiment of the present invention includes compounds ofFormula (II) wherein

[0556] R⁵ is independently selected from the group consisting of: alkyl,alkyloxy, —C(═O)NH₂, —C(═O)Oalkyl, —C(═O)OH, cyano, dialkylamino,halogen, halogenated alkyl, halogenated alkyloxy, halogenated thioalkyl,hydroxy, hydroxy alkyl, nitro, —SO₂NH₂, thioalkyl,

[0557] and —V—B¹⁰—W—B²⁰.

[0558] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0559] R⁵ is independently selected from the group consisting of:methyl, ethyl, isopropyl, t-butyl, methoxy, ethoxy, —C(═O)NH₂,—C(═O)Omethyl, —C(═O)Oethyl, —C(═O)OH, cyano, dimethyl-amino, bromo,chloro, fluoro, trifluoromethyl, trifluoromethoxy, thio-trifluoromethyl,hydroxy, hydroxymethyl, hydroxyethyl, nitro, —SO₂NH₂, thiomethyl

[0560] and —V—B¹⁰—W—B²⁰.

[0561] An embodiment of the present invention includes compounds ofFormula (II):

[0562] wherein V and W are each independently absent or selected fromthe group consisting of: —C(═O), —C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—,—NH—, —NHC(═O)—, —NHC(═O)NH—, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O),—OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—, and —SO₂NH—.

[0563] An embodiment of the present invention includes compounds ofFormula (II):

[0564] wherein V and W are each independently absent or selected fromthe group consisting of: —C(═O), —C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—,—NH—, —O— and —SO₂—.

[0565] An embodiment of the present invention includes compounds ofFormula (II) wherein V is absent or selected from the group consistingof: —C(═O), —C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —NH—, —O— and —SO₂—.

[0566] An embodiment of the present invention includes compounds ofFormula (II) wherein V is absent or selected from the group consistingof: —C(═O)NH—, —C(═O)O—, —NH—, —O— and —SO₂—.

[0567] An embodiment of the present invention includes compounds ofFormula (II) wherein W is absent.

[0568] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0569] B¹⁰ is absent or alkyl; and

[0570] wherein when B¹⁰ is alkyl, the alkyl may be optionallysubstituted with one or more groups independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated —SO₂alkyl, halogenated thioalkyl, hydroxy—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl.

[0571] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0572] B¹⁰ is absent or alkyl; and

[0573] wherein when B¹⁰ is alkyl, the alkyl may be optionallysubstituted with one or more groups independently selected from: alkoxy,alkylamino, amino, dialkylamino, halogen, halogenated alkoxy, hydroxy—NHC(═O)NH₂, —NHSO₂alkyl, —SO₂alkyl or thioalkyl.

[0574] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0575] B¹⁰ is absent or selected from methyl or ethyl,; wherein methylor ethyl are optionally substituted with one or more groupsindependently selected from dialkylamino or hydroxy.

[0576] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0577] B¹⁰ is absent or selected from methyl or ethyl,; wherein methylor ethyl are optionally substituted with one or more groupsindependently selected from dimethyl-amino or hydroxy.

[0578] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0579] B²⁰ is absent or selected from alkyl, alkenyl, or H;

[0580] wherein, when B²⁰ is alkyl or alkenyl, the alkyl or alkenyl groupmay be optionally substituted with one or more groups independentlyselected from: alkoxy, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkoxy, halogenated —SO₂alkyl, halogenated thioalkyl,hydroxy —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl.

[0581] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0582] B²⁰ is absent or selected from alkyl, alkenyl, or H;

[0583] wherein, when B²⁰ is alkyl or alkenyl, the alkyl or alkenyl groupmay be optionally substituted with one or more groups independentlyselected from: alkoxy, alkylamino, amino, dialkylamino, halogen,halogenated alkoxy, hydroxy, —NHC(═O)NH₂, —NHSO₂alkyl or thioalkyl.

[0584] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0585] B²⁰ is absent or H.

[0586] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0587] is selected from the group consisting of aryl, cycloalkyl,partially unsaturated carbocycle, heteroaryl and heterocycloalkyloptionally substituted with one or more substituents independentlyselected from alkoxy, alkyl, alkylamino, amino, cyano, dialkylamino,halogen, halogenated alkoxy, halogenated alkyl, halogenated —SO₂alkyl,halogenated thioalkyl, heteroaryl, hydroxy, hydroxy alkyl,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —SO₂alkyl, thio orthioalkyl.

[0588] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0589] is selected from the group consisting of phenyl, imidazolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, morpholinyl, piperazinyl andpiperidinyl optionally substituted with one or more substituentsindependently selected from alkoxy, alkyl, alkylamino, amino, cyano,dialkylamino, halogen, halogenated alkoxy, halogenated alkyl,halogenated —SO₂alkyl, halogenated thioalkyl, heteroaryl, hydroxy,hydroxy alkyl, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—SO₂alkyl, thio or thioalkyl.

[0590] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0591] is selected from the group consisting of phenyl, imidazolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, morpholinyl, piperazinyl andpiperidinyl optionally substituted with one or more substituentsindependently selected from alkoxy, alkyl, alkylamino, amino,dialkylamino, halogen, halogenated alkoxy, halogenated alkyl,heteroaryl, hydroxy, hydroxy alkyl, —NHC(═O)NH₂, —NHSO₂alkyl, nitro or—SO₂alkyl.

[0592] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0593] is selected from the group consisting of phenyl, imidazolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, morpholinyl, piperazinyl andpiperidinyl optionally substituted with one or more substituentsindependently selected from methoxy, ethoxy, methyl, ethyl, bromo,chloro, fluoro, trifluoromethyl, pyridinyl, hydroxy or hydroxymethyl.

[0594] A embodiment of the present invention includes compounds ofFormula (II) wherein:

[0595] is selected from the group consisting of:1-(3-methoxy-phenyl)-(S*)ethyl; 2-(3-bromo)-pyridyl;2-(3-methyl)-pyridyl; 2-(3-methyl-5-bromo)-pyridyl;2-(4,6-dimethyl)-pyridyl; 2-(4-bromo)-pyridyl; 2-(piperidin-1-yl)-ethyl;2,2-difluoro-1,3-benzodioxol-4-yl; 2,3-dichloro-benzyl;2,3-dichloro-phenyl; 2,3-dihydro-1H-indol-1-yl; 2,3-dimethoxy-benzyl;2,4,6-trifluoro-phenyl; 2,4-dichloro-phenyl; 2,4-difluoro-benzyl;2,4-dimethoxy-phenyl; 2,4-dimethoxy-phenyl; 2,5-dichloro-benzyl;2,5-dichloro-phenyl; 2,5-difluoro-benzyl; 2,5-difluoro-phenyl;2,5-dimethoxy-benzyl; 2,5-dimethoxy-phenyl; 2,6-dichloro-benzyl;2,6-difluoro-benzyl; 2,6-difluoro-phenyl; 2-bromo-3-fluoro-phenyl;2-bromo-benzyl; 2-bromo-phenyl; 2-chloro-benzyl; 2-chloro-phenyl;2-ethyl-phenyl; 2-fluoro-benzyl; 2-fluoro-phenyl; 2-furyl;2-isopropyl-phenyl; 2-methoxy-benzyl; 2-methoxy-phenyl; 2-methyl-benzyl;2-methyl-phenyl; 2-morpholin-4-yl-ethyl; 2-pyridyl; 2-pyridyl-methyl;2-trifluoromethoxy-benzyl; 2-trifluoromethoxy-phenyl;2-trifluoromethyl-4-bromo-phenyl; 2-trifluoromethyl-benzyl;2-trifluoromethyl-phenyl; 3-(1-hydroxy-ethyl)-phenyl;3-(2,4-dimethoxy)-pyridyl; 3-(2-chloro)-pyridyl;3-(2-hydroxy-ethyl-amino-carbonyl)-phenyl; 3-(4-methoxy)-pyridyl;3-(4-methyl-piperazinyl-carbonyl)-phenyl; 3-(4-trifluoromethyl)-pyridyl;3-(amino-carbonyl)-phenyl; 3-(amino-sulfonyl)-phenyl;3-(ethoxy-carbonyl)-phenyl; 3-(methoxy-carbonyl)-phenyl;3-(trifluoromethyl-thio)-phenyl; 3,4,5-trimethoxy-phenyl;3,4-dichloro-benzyl; 3,4-dichloro-phenyl; 3,4-difluoro-benzyl;3,4-dimethoxy-phenyl; 3,4-dimethyl-benzyl; 3,4-methylenedioxy-phenyl;3,5-di(tert-butyl)-phenyl; 3,5-di(trifluoromethyl)-phenyl;3,5-dichloro-benzyl; 3,5-dichloro-phenyl; 3,5-difluoro-phenyl;3,5-dimethoxy-phenyl; 3,5-dimethyl-phenyl;3-[N-(3-pyrrolidin-1-yl-propyl)-amino-carbonyl]-phenyl;3-benzyloxy-phenyl; 3-bromo-phenyl; 3-carboxy-phenyl;3-chloro-4-fluoro-phenyl; 3-chloro-4-methoxy-phenyl;3-chloro-4-methyl-benzyl; 3-chloro-benzyl; 3-chloro-phenyl;3-cyano-phenyl; 3-ethoxy-phenyl; 3-ethyl-phenyl; 3-fluoro-benzyl;3-fluoro-phenyl; 3-hydroxymethyl-phenyl; 3-hydroxy-phenyl;3-isopropoxy-phenyl; 3-methoxy-5-trifluoromethyl-phenyl;3-methoxy-benzyl; 3-methyl-benzyl; 3-methyl-phenyl; 3-methylthio-phenyl;3-pyridyl; 3-pyridyl-methyl; 3-trifluoromethoxy-phenyl;3-trifluoromethyl-phenyl; 4-(4-methyl-piperazin-1-yl)-phenyl;4-(ethoxy-carbonyl)-phenyl; 4-(N,N-dimethyl-amino)-phenyl;4-(piperidin-4-yl-sulfonyl)-phenyl; 4-benzyloxy-phenyl; 4-bromo-phenyl;4-chloro-3-methyl-benzyl; 4-chloro-phenyl; 4-cyano-phenyl;4-dimethylamino-phenyl; 4-fluoro-3-chloro-phenyl;4-fluoro-3-nitro-phenyl; 4-fluoro-3-trifluoromethyl-phenyl;4-fluoro-benzyl; 4-fluoro-phenyl; 4-methoxy-benzyl;4-methyl-3-[N-[4-(3-pyridyl)-pyrimidin-2-yl]amino]-phenyl;4-methyl-benzyl; 4-methyl-phenyl; 4-trifluoromethoxy-phenyl;4-trifluoromethyl-phenyl; 5-(phenyl)-isoxazol-3-yl-methyl;5-bromo-2,3-dihydro-1H-indol-1-yl; 5-chloro-2-methoxy-phenyl;5-chloro-2-methyl-phenyl; 5-indanyl; 5-indolyl; 5-indolyl;5-trifluoromethyl-2-fluoro-phenyl; 6-indazolyl; benzyl; cyclohexyl;cyclohexyl-methyl; and phenyl.

[0596] 2.a.2

[0597] An embodiment of the present invention includes compounds ofFormula (II) wherein:

[0598] is selected from the group consisting of Formulae A-1, A-2 andA-3:

[0599] wherein Formula A-1 is attached on the b¹ side of Formula A-1 tothe L² ring of Formula (II) and optionally substituted with onesubstituent selected from the group consisting of Formulae A-1-a, A-1-band A-1-c:

[0600] wherein Formula A-1-a is attached on the a¹ side to adjacentcarbons on the d¹or d² side of Formula A-1;

[0601] wherein Formula A-1-b is attached on the a² side to adjacentcarbons on the d¹or d² side of Formula A-1;

[0602] wherein Formula A-1-c is attached on the a⁶ side to adjacentcarbons on the d¹or d² side of Formula A-1;

[0603] wherein R⁸ is H or lower alkyl;

[0604] wherein Formula A-2 is selected from the group consisting ofpyridyl and pyrimidinyl; is attached on the b² side of Formula A-2 tothe L² ring of Formula (II); and is optionally substituted on a carbonring member with H or alkoxy, wherein the alkoxy may be optionallyfurther substituted with alkoxy on a terminal carbon or up to 3 halogenatoms on a terminal carbon; and

[0605] wherein Formula A-3 is selected from the group consisting ofthienyl, isoxazolyl and furyl; is attached on the b³ side of Formula A-3to the L² ring of Formula (II), and is optionally substituted on acarbon ring member with C₁₋₄alkyl, aryl, alkoxy, or halogen;

[0606] s is an integer from 0 to 2; and

[0607] m is an integer from 0 to 4; provided that when

[0608] is not substituted with Formulae A-1-a, A-1-b or A-1-c, the sumof m and s is an integer from 0 to 4, and when

[0609] is substituted with one of Formulae A-1-a, A-1-b, or A-1-c, thesum of m and s is an integer from 0 to 2;

[0610] R⁹ is independently selected from the group consisting of:alkoxy, alkyl, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkyl, halogenated alkyloxy, hydroxy, —NHC(═O)alkyl,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, and thioalkyl;

[0611] L² is a linking group selected from the group consisting of:—(CH₂)—, —(CH₂)₃₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—,—O(CH₂)₁₋₄—, —OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-,—N(COalkyl)-, —N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and—N(SO₂aryl)-; provided that when L² is —O—, neither R⁶ nor R⁷ is —CH₃;

[0612] R¹⁰⁰ is selected from: alkyl, hydroxy, aryl, oxo or ═N(OH);

[0613] R¹⁰ is independently selected from the group consisting of

[0614] —X¹-A²⁰-Y¹-A²¹, —X¹-A²⁰-A²¹, —X¹-A²¹, -A²⁰-A²¹ and -A²¹,

[0615] wherein

[0616] X¹ and Y¹ are each independently absent or selected from thegroup consisting of: —NH—, —O—, —SO₂— and —SO₂NH—;

[0617] A²⁰ is absent or alkyl;

[0618] wherein when A²⁰ is alkyl, the alkyl may be optionallysubstituted with one or more groups independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated —SO₂alkyl, halogenated thioalkyl, hydroxy,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl;

[0619] A²¹ is selected from alkyl, alkenyl, or H;

[0620] wherein when A²¹ is alkyl or alkenyl, the alkyl or alkenyl may beoptionally substituted with one or more groups independently selectedfrom: alkoxy, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkoxy, halogenated —SO₂alkyl, halogenated thioalkyl,hydroxy, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl,—OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio orthioalkyl; and

[0621] is selected from the group consisting of aryl, cycloalkyl,partially unsaturated carbocycle, heteroaryl and heterocycloalkyloptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, amino, thio, nitro, cyano, alkyl,halogenated alkyl, alkoxy, halogenated alkoxy, alkylamino,—NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, or dialkylamino, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —OC(═O)NHalkyl, —NHC(═O)Oalkyl,—N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl, —N(alkyl)SO₂alkyl, thioalkyl,halogenated thioalkyl, —SO₂alkyl, halogenated —SO₂alkyl,—NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or —OC(═O)N(alkyl)₂;

[0622] R⁶ and R⁷ are independently selected from the group consistingof:

[0623] (a)

[0624] (b)

[0625] provided that R⁴ is not

[0626] (c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —(C═O)OH, —C(═O)Oalkyl,—C(═O)Oaryl, —C(═O)Oheteroaryl, —(C═O)NH₂, —(C═O)NHalkyl,—(C═O)N(alkyl)₂, —C(═O)alkyl, -phenyl-OCH₃ or -phenyl-OC(═O)alkyl;

[0627] (d) —C(═O)(CH₂CH₂O—)₁₋₁₀ terminating with H;

[0628] (e) —C(═O)CH₂O(CH₂CH₂O—)₁₋₁₀ terminating with H;

[0629] (f) —C(═O)alkyl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —Oalkylaryl, —NH₂, —NHalkyl,—N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, or—OC(═O)alkyl;

[0630] (g) —C(═O)(CH₂)₁₋₃aryl or —C(═O)aryl, wherein said —C(═O)aryl maybe optionally substituted with one or more groups independently selectedfrom: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl,—NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl;

[0631] (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with methyl, ethyl, —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, or heterocycloalkyl;

[0632] (hh) —C(═O)alkylOC(═O)alkyl-terminating with —OH, —Oalkyl, —NH₂,—NHalkyl or —N(alkyl)₂;

[0633] (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, orbenzyl;

[0634] —C(═O)Oalkyloptionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, —OC(═O)alkyl, —C(═O)OH,—C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂;

[0635] (k) —C(═O)O(CH₂)₁₋₃aryl or —C(═O)Oaryl, wherein said —C(═O)Oarylmay be optionally substituted with one or more groups independentlyselected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile,or-OC(═O)alkyl;

[0636] (l) —C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H, methyl, ethyl,benzyl,—CH₂CH₂NH₂, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂,—CH₂CH₂-1-pyrrolidinyl, —CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl,—CH₂CH₂-1-piperazinyl, —CH₂CH₂-1-(4-CH₃)-piperazinyl or —C(═O)alkyl;

[0637] (m) —C(═O)NH₂, —C(═O)NH(C₁₋₂₀)alkyl, or —C(═O)N(C₁₋₂₀alkyl)₂,wherein said —C(═O)NH(C₁₋₂₀)alkyl, may be optionally substituted withone or more groups independently selected from: —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl,—OC(═O)alkyl, —OC(═O)alkenyl, —NHC(═O)aryl, —C(═O)OH, —C(═O)Oalkyl,—C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂; and, wherein the arylportion of said —NHC(═O)aryl may be optionally substituted with one ormore groups independently selected from: alkyl, —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, halogen or nitrile;

[0638] (n) —C(═O)NH(CH₂)₁₋₃aryl or —C(═O)NHaryl, wherein said—C(═O)NHaryl may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl )₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl;

[0639] (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with H, methyl,ethyl, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃,—CH₂CH₂OC(═O)alkyl or —C(═O)aryl; wherein the aryl portion of said—C(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile;

[0640] (p) —C(═S)NH₂;

[0641] (q) —C(═S)NHalkyl;

[0642] (r) —C(═S)N(alkyl)₂;

[0643] (s) —SO₂NH₂;

[0644] (t) —SO₂NHalkyl;

[0645] (u) —SO₂N(alkyl)₂;

[0646] (v) —P(═O)(OCH₃)₂; and

[0647] (w) —P(═O)(OCH₂CH₃)₂;

[0648] provided that when R⁶ is present, R⁷ is absent; and provided thatwhen R⁷ is present, R⁶ is absent;

[0649] R⁴ is selected from the group consisting of: H and

[0650] provided that if one of R⁶and R⁷ is

[0651] then R⁴ is H;

[0652] L³ is absent or is a linking group selected from the groupconsisting of methylene, ethylene, carbonyl or —SO₂—;

[0653] is selected from the group consisting of an aryl, a cycloalkyl, aheteroaryl, a heterocycloalkyl, a nine to ten membered benzo-fusedcycloalkyl, a nine to ten membered benzo-fused heteroaryl, and a nine toten membered benzo-fused heterocycloalkyl;

[0654] r is an integer from 0 to 4; and

[0655] R⁵ is independently selected from the group consisting of: alkyl,alkyloxy, amino, —C(═O)NH₂, —C(═O)Oalkyl, —C(═O)OH, cyano, dialkylamino,halogen, halogenated alkyl, halogenated alkyloxy, halogenated thioalkyl,hydroxy, hydroxy alkyl, —NHC(═O)NH₂, —NHSO₂alkyl, nitro, —SO₂alkyl,—SO₂NH₂, thio, thioalkyl,

[0656] and —V—B¹⁰—W—B²⁰;

[0657] wherein

[0658] V and W are each independently absent or selected from the groupconsisting of: —C(═O), —C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —NH—,—NHC(═O)—, —NHC(═O)NH—, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)NH—,—OC(═O)O—, —S—, —SO—, —SO₂—, and —SO₂NH—;

[0659] B¹⁰ is absent or alkyl;

[0660] wherein when B¹⁰ is alkyl, the alkyl may be optionallysubstituted with one or more groups independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated —SO₂alkyl, halogenated thioalkyl, hydroxy—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl;

[0661] B²⁰ is absent or selected from alkyl, alkenyl, or H;

[0662] wherein, when B²⁰ is alkyl or alkenyl, the alkyl or alkenyl groupmay be optionally substituted with one or more groups independentlyselected from: alkoxy, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkoxy, halogenated —SO₂alkyl, halogenated thioalkyl,hydroxy —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl; and

[0663] is selected from the group consisting of aryl, cycloalkyl,partially unsaturated carbocycle, heteroaryl and heterocycloalkyloptionally substituted with one or more substituents independentlyselected from alkoxy, alkyl, alkylamino, amino, cyano, dialkylamino,halogen, halogenated alkoxy, halogenated alkyl, halogenated —SO₂alkyl,halogenated thioalkyl, heteroaryl, hydroxy, hydroxy alkyl,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, -SO₂alkyl, thio orthioalkyl;

[0664] or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof.

[0665] An embodiment of the present invention includes compounds ofFormula (II) wherein

[0666] is selected from the group consisting of:

[0667] wherein Formula A-4 is attached on the b¹ side of Formula A-4 tothe L² ring of Formula (II);

[0668] wherein Formula A-5 is attached on the b¹ side of Formula A-5 tothe L² ring of Formula (II); wherein R⁸ is H and lower alkyl;

[0669] wherein Formula A-6 is attached on the b¹ side of Formula A-6 tothe L² ring of Formula (II); and

[0670] wherein Formula A-3-a is attached on the b³ side of Formula A-3-ato the L² ring of formula (II), wherein R¹² is independently selectedfrom H, methyl, phenyl, ethoxy, chloro or fluoro;

[0671] s is an integer from 0 to 2; and

[0672] m is an integer from 0 to 4; provided that when

[0673] is Formula A-4, the sum of m and s is an integer from 0 to 4, andwhen

[0674] is Formulae A-5 or A-6, the sum of m and s is an integer from 0to 2;

[0675] R⁹ is independently selected from the group consisting of:alkoxy, alkyl, amino, cyano, dialkylamino, halogen, halogenated alkyl,halogenated alkyloxy, hydroxy and —NHC(═O)alkyl;

[0676] L² is a linking group selected from the group consisting of:—(CH₂)—, —(CH₂)₃₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;

[0677] R¹⁰⁰ is selected from: alkyl, hydroxy, aryl, oxo or ═N(OH);

[0678] R¹⁰ is independently selected from the group consisting of

[0679] —X¹-A²⁰-Y¹-A²¹, —X¹-A²⁰-A²¹ and —X¹A²¹, wherein

[0680] X¹ and Y¹ are each independently absent or —O—;

[0681] A²⁰ is absent or alkyl;

[0682] wherein when A²⁰ is alkyl, the alkyl may be optionallysubstituted with one or more groups independently selected from: alkoxy,alkylamino, amino, dialkylamino, halogen, halogenated alkoxy, hydroxy,—NHC(═O)NH₂, —NHSO₂alkyl, —SO₂alkyl or thioalkyl;

[0683] A²¹ is selected from alkyl, alkenyl, or H;

[0684] wherein when A²¹ is alkyl or alkenyl, the alkyl or alkenyl may beoptionally substituted with one or more groups independently selectedfrom: alkoxy, alkylamino, amino, dialkylamino, halogen, halogenatedalkoxy, hydroxy, —NHC(═O)NH₂, —NHSO₂alkyl or thioalkyl; and

[0685] is selected from the group consisting of aryl, heteroaryl andheterocycloalkyl optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, amino, thio, nitro, cyano,alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, alkylamino,—NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, or dialkylamino, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —OC(═O)NHalkyl, —NHC(═O)Oalkyl,—N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl, —N(alkyl)SO₂alkyl, thioalkyl,halogenated thioalkyl, —SO₂alkyl, halogenated —SO₂alkyl,—NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or —OC(═O)N(alkyl)₂;

[0686] R⁶ and R⁷ are independently selected from the group consistingof:

[0687] (a)

[0688] (b)

[0689] provided that R⁴ is not

[0690] (c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —(C═O)OH, —C(═O)Oalkyl,—C(═O)Oaryl, —C(═O)Oheteroaryl, —(C═O)NH₂, —(C═O)NHalkyl,—(C═O)N(alkyl)₂, —C(═O)alkyl, -phenyl-OCH₃ or -phenyl-OC(═O)alkyl;

[0691] (f) —C(═O)alkyl optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —Oalkylaryl, —NH₂, —NHalkyl,—N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, or—OC(═O)alkyl;

[0692] (g) —C(═O)(CH₂)₁₋₃aryl or —C(═O)aryl, wherein said —C(═O)aryl maybe optionally substituted with one or more groups independently selectedfrom: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl,—NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl;

[0693] (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with methyl, ethyl, —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, or heterocycloalkyl;

[0694] (hh) —C(═O)alkylOC(═O)alkyl-terminating with —OH, —Oalkyl, —NH₂,—NHalkyl or —N(alkyl)₂;

[0695] (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, orbenzyl;

[0696] (j) —C(═O)Oalkyloptionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, —OC(═O)alkyl, —C(═O)OH,—C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂;

[0697] (k) —C(═O)O(CH₂)₁₋₃aryl or —C(═O)Oaryl, wherein said —C(═O)Oarylmay be optionally substituted with one or more groups independentlyselected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl;

[0698] (l) —C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H, methyl, ethyl,benzyl,—CH₂CH₂NH₂, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂,—CH₂CH₂-1-pyrrolidinyl, —CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl,—CH₂CH₂-1-piperazinyl, —CH₂CH₂-1-(4-CH₃)-piperazinyl or —C(═O)alkyl;

[0699] (m) —C(═O)NH₂, —C(═O)NH(C₁₋₂₀)alkyl, or —C(═O)N(C₁₋₂₀alkyl)₂,wherein said —C(═O)NH(C₁₋₂₀)alkyl, may be optionally substituted withone or more groups independently selected from: —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl,—OC(O)alkyl, —OC(═O)alkenyl, —NHC(═O)aryl, —C(═O)OH, —C(═O)Oalkyl,—C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂; and, wherein the arylportion of said —NHC(═O)aryl may be optionally substituted with one ormore groups independently selected from: alkyl, —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, halogen or nitrile;

[0700] (n) —C(═O)NH(CH₂)₁₋₃aryl or —C(═O)NHaryl, wherein said—C(═O)NHaryl may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl;

[0701] (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with H, methyl,ethyl, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃,—CH₂CH₂OC(═O)alkyl, or —C(═O)aryl; wherein the aryl portion of said—C(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile;

[0702] (p) —C(═S)NH₂;

[0703] (u) —SO₂N(alkyl)₂; and

[0704] (w) —P(═O)(OCH₂CH₃)₂;

[0705] provided that when R⁶ is present, R⁷ is absent; and provided thatwhen R⁷ is present, R⁶ is absent;

[0706] R⁴ is selected from the group consisting of: H and A

[0707] provided that if one of R⁶ and R⁷ is

[0708] then R⁴ is H;

[0709] L³ is absent or is a linking group selected from the groupconsisting of methylene, ethylene or carbonyl;

[0710] is selected from the group consisting of an aryl, a cycloalkyl, aheteroaryl, a heterocycloalkyl, a nine to ten membered benzo-fusedcycloalkyl and a nine to ten membered benzo-fused heterocycloalkyl;

[0711] r is an integer from 0 to 4; and

[0712] R⁵ is independently selected from the group consisting of: alkyl,alkyloxy, —C(═O)NH₂, —C(═O)Oalkyl, —C(═O)OH, cyano, dialkylamino,halogen, halogenated alkyl, halogenated alkyloxy, halogenated thioalkyl,hydroxy, hydroxy alkyl, nitro, —SO₂NH₂, thioalkyl,

[0713] and —V—B¹⁰—W—B²⁰; wherein

[0714] V and W are each independently absent or selected from the groupconsisting of: —C(═O), —C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —NH—, —O—and —SO₂—;

[0715] B¹⁰ is absent or alkyl;

[0716] wherein when B¹⁰ is alkyl, the alkyl may be optionallysubstituted with one or more groups independently selected from: alkoxy,alkylamino, amino, dialkylamino, halogen, halogenated alkoxy, hydroxy—NHC(═O)NH₂, —NHSO₂alkyl, —SO₂alkyl or thioalkyl;

[0717] B²⁰ is absent or selected from alkyl, alkenyl, or H;

[0718] wherein, when B²⁰ is alkyl or alkenyl, the alkyl or alkenyl groupmay be optionally substituted with one or more groups independentlyselected from: alkoxy, alkylamino, amino, dialkylamino, halogen,halogenated alkoxy, hydroxy, —NHC(═O)NH₂, —NHSO₂alkyl or thioalkyl; and

[0719] is selected from the group consisting of phenyl, imidazolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, morpholinyl, piperazinyl andpiperidinyl optionally substituted with one or more substituentsindependently selected from alkoxy, alkyl, alkylamino, amino, cyano,dialkylamino, halogen, halogenated alkoxy, halogenated alkyl,halogenated —SO₂alkyl, halogenated thioalkyl, heteroaryl, hydroxy,hydroxy alkyl, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—SO₂alkyl, thio or thioalkyl;

[0720] or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof.

[0721] 2.b Formulae (II-AA) Through (II-JJ)

[0722] The present invention is further directed to compounds of Formula(II-AA)

[0723] wherein:

[0724] R¹⁰⁰ is selected from the group consisting of: H and alkyl;

[0725] R^(B) and R^(C) are independently selected from the groupconsisting of: alkoxy; and

[0726] R⁵ is selected from the group consisting of: alkoxy and halogen;

[0727] or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof.

[0728] A preferred embodiment of the present invention includescompounds of Formula (II-AA) wherein R¹⁰⁰ is selected from the groupconsisting of: H, methyl, ethyl; R^(B) and R^(C) are independentlyselected from the group consisting of: methoxy and ethoxy; and R⁵ isselected from the group consisting of: methoxy, ethoxy, isopropoxy,chloro, bromo, and fluoro.

[0729] The present invention is further directed to compounds of Formula(II-BB)

[0730] wherein

[0731] R^(C) is —O(CH₂)₃OH;

[0732] R¹⁰⁰ is selected from the group consisting of: H and alkyl;

[0733] R^(B) is selected from the group consisting of: alkoxy; and

[0734] R⁵ is selected from the group consisting of: alkoxy and halogen;

[0735] or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof.

[0736] A preferred embodiment of the present invention includescompounds of Formula (II-BB) wherein R¹⁰⁰ is selected from the groupconsisting of: H, methyl, ethyl; R^(B) is selected from the groupconsisting of: methoxy and ethoxy; and R⁵ is selected from the groupconsisting of: methoxy, ethoxy, isopropoxy, chloro, bromo, and fluoro.

[0737] The present invention is further directed to compounds of Formula(II-CC)

[0738] wherein

[0739] R¹⁰⁰ is selected from the group consisting of: H and alkyl;

[0740] R^(B) and R^(C) are independently selected from the groupconsisting of: alkoxy; and R⁵ is selected from the group consisting of:alkyl, cyano, hydroxy, alkoxy and halogen;

[0741] or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof.

[0742] A preferred embodiment of the present invention includescompounds of Formula (II-CC) wherein R¹⁰⁰ is selected from the groupconsisting of: H, methyl, ethyl; R^(B) and R^(C) are independentlyselected from the group consisting of: methoxy and ethoxy; and R⁵ isselected from the group consisting of: methoxy, ethoxy, isopropoxy,chloro, methyl, cyano and hydroxy.

[0743] The present invention is further directed to compounds of Formula(II-DD)

[0744] wherein

[0745] R^(C) is —O(CH₂)₃OH;

[0746] R¹⁰⁰ is selected from the group consisting of: H and alkyl;

[0747] R^(B) is selected from the group consisting of: alkoxy; and

[0748] R⁵ is selected from the group consisting of: alkyl, cyano,hydroxy, alkoxy and halogen;

[0749] or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof.

[0750] A preferred embodiment of the present invention includescompounds of Formula (II-DD) wherein R¹⁰⁰ is selected from the groupconsisting of: H, methyl, and ethyl; R^(B) is selected from the groupconsisting of: methoxy and ethoxy; and R⁵ is selected from the groupconsisting of: methoxy, ethoxy, isopropoxy, chloro, methyl, cyano andhydroxy.

[0751] The present invention is further directed to compounds of Formula(II-EE)

[0752] wherein

[0753] R⁵ is selected from the group consisting of: alkoxy and halogen;and

[0754] R^(C) is selected from the group consisting of: alkoxy,

[0755] or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof.

[0756] In a preferred embodiment, the present invention is furtherdirected to compounds of Formula (II-FF)

[0757] wherein

[0758] R⁹ is independently selected from the group consisting of:alkoxy, alkyl, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkyl, halogenated alkyloxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy, —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —SO₂alkyl, thio and thioalkyl;

[0759] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;wherein R¹⁰⁰ is selected from: alkyl, hydroxy, aryl, alkoxy, oxo, —NH₂,—NH(alkyl) —N(alkyl)₂, ═N(OH) or —NH₂OH; provided that when L² is—CH₂CH₂—, neither R⁶ nor R⁷ is —CH₂—(C═O)NHalkyl, —CH₂—(C═O)N(alkyl)₂ or—CH₂C(═O)Oalkyl; provided that when L² is —OCH(R¹⁰⁰)—, R¹⁰⁰ is alkoxy,and

[0760] is phenyl, R⁵ is not —C(═O)NH—NH₂; and provided that when L² is—O— or —S—, neither R⁶ nor R⁷ is —CH₃;

[0761] R¹⁰ is independently selected from the group consisting of

[0762] and —X¹-A²⁰-Y¹-A²¹;

[0763] wherein X¹ and Y¹ are each independently absent or selected fromthe group consisting of: —(alkyl)C(═O)N(alkyl)-, —C(═O)N(alkyl)-,—C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-,—NHC(═O)NH, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-,—OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)-, and —SO₂NH—;

[0764] A²⁰ is absent or selected from alkyl or alkenyl; and

[0765] A²¹ is selected from alkyl, alkenyl, or H;

[0766] wherein when A²⁰ or A²¹ is alkyl or alkenyl, the alkyl or alkenylmay be optionally substituted with one or more groups independentlyselected from: alkoxy, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkoxy, halogenated —SO₂alkyl, halogenated thioalkyl,hydroxy, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl,—OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio orthioalkyl;

[0767] s selected from the group consisting of aryl, cycloalkyl,partially unsaturated carbocycle, heteroaryl, heterocycloalkyl, nine toten membered benzo-fused cycloalkyl, and nine to ten memberedbenzo-fused heterocycloalkyl; wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, are optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, amino, thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy,halogenated alkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, ordialkylamino, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂;

[0768] s is an integer from 0 to 2;

[0769] m is an integer from 0 to 4; provided that the sum of m and s isan integer from 0 to 4;

[0770] R⁶ and R⁷ are independently selected from the group consistingof:

[0771] (a)

[0772] (b)

[0773] provided that R⁴ is not

[0774] (c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —(C═O)OH, —C(═O)Oalkyl,—C(═O)Oaryl, —C(═O)Oheteroaryl, —(C═O)NH₂, —(C═O)NHalkyl,—(C═O)N(alkyl)₂, —C(═O)alkyl, -phenyl-OCH₃ or -phenyl-OC(═O)alkyl;

[0775] (d) —C(═O)(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, orbenzyl;

[0776] (e) —C(═O)CH₂O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl,or benzyl;

[0777] (f) —C(═O)alkyl, or —C(═O)(C₃₋₆)cycloalkyl, wherein said—C(═O)alkyl, and —C(═O)(C₃₋₆)cycloalkyl may be optionally substitutedwith one or more groups independently selected from: —OH, —Oalkyl,—Oalkylaryl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl,—NHC(═O)alkyl, —NHSO₂alkyl, or —OC(═O)alkyl;

[0778] (g) —C(═O)(CH₂)₁₋₃aryl, —C(═O)aryl, —C(═O)(CH₂)₁₋₃heteroaryl, or—C(═O)heteroaryl, wherein said —C(═O)(CH₂)₁₋₃aryl, —C(═O)aryl,—C(═O)(CH₂)₁₋₃heteroaryl, and —C(═O)heteroaryl may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl;

[0779] (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with methyl, ethyl, —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, or heterocycloalkyl;

[0780] (hh) —C(═O)alkylOC(═O)alkyl-terminating with —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, or heterocycloalkyl;

[0781] (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, orbenzyl;

[0782] (j) —C(═O)Oalkyl, or —C(═O)O(C₃₋₆)cycloalkyl, wherein said—C(═O)Oalkyl, and —C(═O)O(C₃₋₆)cycloalkyl may be optionally substitutedwith one or more groups independently selected from: —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl,—OC(═O)alkyl, —C(═O)OH, —C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or—C(═O)N(alkyl)₂;

[0783] (k) —C(═O)O(CH₂)₁₋₃aryl, —C(═O)Oaryl, —C(═O)O(CH₂)₁₋₃heteroaryl,or —C(═O)Oheteroaryl, wherein said —C(═O)O(CH₂)₁₋₃aryl, —C(═O)Oaryl,—C(═O)O(CH₂)₁₋₃heteroaryl, or —C(═O)Oheteroaryl may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl;

[0784] (l) —C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H, methyl, ethyl,benzyl, —CH₂CH₂NH₂, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂,—CH₂CH₂-1-pyrrolidinyl, —CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl,—CH₂CH₂-1-piperazinyl, —CH₂CH₂-1-(4-CH₃)-piperazinyl or —C(═O)alkyl;

[0785] (m) —C(═O)NH₂, —C(═O)NH(C₁₋₂₀)alkyl, —C(═O)NH(C₃₋₆)cycloalkyl, or—C(═O)N(alkyl)₂, wherein said —C(═O)NH(C₁₋₂₀)alkyl,—C(═O)NH(C₃₋₆)cycloalkyl, and —C(═O)N(alkyl)₂ may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)alkenyl, —NHC(═O)aryl, —C(═O)OH,—C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂; and, whereinthe aryl portion of said —NHC(═O)aryl may be optionally substituted withone or more groups independently selected from: alkyl, —OH, —Oalkyl,—NH₂, —NHalkyl, —N(alkyl)₂, halogen or nitrile;

[0786] (n) —C(═O)NH(CH₂)₁-₃aryl, —C(═O)NHaryl,—C(═O)NH(CH₂)₁₋₃heteroaryl, or —C(═O)NHheteroaryl, wherein said—C(═O)NH(CH₂)₁-3aryl, —C(═O)NHaryl, —C(═O)NH(CH₂)₁-₃heteroaryl, and—C(═O)NHheteroaryl may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl;

[0787] (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with H, methyl,ethyl, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃,—CH₂CH₂OC(═O)alkyl, or —C(═O)aryl; wherein the aryl portion of said—C(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile;

[0788] (p) —C(═S)NH₂;

[0789] (q) —C(═S)NHalkyl;

[0790] (r) —C(═S)N(alkyl)₂;

[0791] (s) —SO₂NH₂;

[0792] (t) —SO₂NHalkyl;

[0793] (u) —SO₂N(alkyl)₂;

[0794] (v) —P(═O)(OCH₃)₂; and

[0795] (w) —P(═O)(OCH₂CH₃)₂;

[0796] provided that when R⁶ is present, R⁷ is absent; and provided thatwhen R⁷ is present, R⁶ is absent;

[0797] R⁴ is selected from the group consisting of: H and

[0798] provided that if one of R⁶ and R⁷ is

[0799] then R⁴ is H;

[0800] L³ is absent or is a linking group selected from the groupconsisting of alkyldiyl, carbonyl or —SO₂—;

[0801] is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, aralkyl, a heteroaryl, aheterocycloalkyl, a nine to ten membered benzo-fused cycloalkyl, a nineto ten membered benzo-fused heteroaryl, and a nine to ten memberedbenzo-fused heterocycloalkyl;

[0802] r is an integer from 0 to 4; and

[0803] R⁵ is independently selected from the group consisting of: alkyl,alkyl amino, alkyloxy, amino, —C(═O)NH₂, —C(═O)Oalkyl, —C(═O)OH, —CH₂OH,cyano, dialkylamino, halogen, halogenated alkyl, halogenated alkyloxy,halogenated SO₂-alkyl, halogenated thioalkyl, hydroxy, hydroxy alkyl,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —SO₂alkyl,—SO₂NH₂, thio, thioalkyl,

[0804] and —V—B¹⁰—W—B²⁰;

[0805] wherein,

[0806] V and W are each independently absent or selected from the groupconsisting of: —C(═O), —C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —N(alkyl)-,—N(alkyl)C(═O)—, —N(alkyl)C(═O)N(alkyl)-, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-,—NHC(═O)NH—, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-,—OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)- and —SO₂NH—;

[0807] B¹⁰ is absent or selected from alkyl or alkenyl;

[0808] B²⁰ is absent or selected from alkyl, alkenyl, or H;

[0809] wherein, when B¹⁰ or B²⁰ is alkyl or alkenyl, the alkyl oralkenyl group may be optionally substituted with one or more groupsindependently selected from: alkoxy, alkylamino, amino, cyano,dialkylamino, halogen, halogenated alkoxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl; and

[0810] is selected from the group consisting of: an aryl, a cycloalkyl,a partially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl,

[0811] wherein, the aryl, cycloalkyl, partially unsaturated carbocycle,heteroaryl, heterocycloalkyl, benzo-fused cycloalkyl, or benzo-fusedheterocycloalkyl, is optionally substituted with one or moresubstituents independently selected from: alkoxy, alkylamino, amino,cyano, dialkylamino, halogen, halogenated alkoxy, halogenated alkyl,halogenated —SO₂alkyl, halogenated thioalkyl, heteroaryl, hydroxy,hydroxy alkyl, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—SO₂alkyl, thio or thioalkyl;

[0812] or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof.

[0813] Further embodiments of the invention include compounds of FormulaII-FF wherein L², R⁴, R⁶, R⁷, L³ H, and (R⁵)_(r) vary as set forth insection 2.a.1 above for Formula II and combinations of the variationsthereof.

[0814] In a preferred embodiment, the present invention is furtherdirected to compounds of Formula (II-GG):

[0815] wherein:

[0816] is selected from the group consisting of Formulae A-1, A-2 andA-3:

[0817] wherein Formula A-1 is attached on the by side of Formula A-1 tothe L² ring of Formula (II-GG) and optionally substituted with onesubstituent selected from the group consisting of Formulae A-1-a, A-1-band A-1-c:

[0818] wherein Formula A-1-a is attached on the a¹ side to adjacentcarbons on the d¹or d² side of Formula A-1;

[0819] wherein Formula A-1-b is attached on the a²side to adjacentcarbons on the d¹or d² side of Formula A-1; and

[0820] wherein Formula A-1-c is attached on the a⁶ side to adjacentcarbons on the d¹or d² side of Formula A-1;

[0821] wherein R⁸ is H or alkyl;

[0822] wherein Formula A-2 is attached on the b² side of Formula A-2 tothe L² ring of Formula (II-GG), and A¹, A², A³, A⁴ are (i) —N—; or (ii)—C— substituted with H or alkoxy, wherein the alkoxy may be optionallyfurther substituted with alkoxy on a terminal carbon or up to 3 halogenatoms on a terminal carbon; provided that at least one and no more thantwo of A¹, A², A³, A⁴ are —N—; and

[0823] wherein Formula A-3 is attached on the b³ side of Formula A-3 tothe L² ring of Formula (II-GG), and B¹, B² and B³ are independently (i)—CH— optionally substituted with alkyl, aryl, alkoxy, or halogen, (ii)—S—; (iii) —O—; or (iv) —N—; provided that no more than one of B¹, B² orB³ is —S-or —O—, and, provided that when one of B¹, B² or B³ is —S-or—O—, then the adjacent ring members are not —S-or —O—;

[0824] R⁹ is independently selected from the group consisting of:alkoxy, alkyl, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkyl, halogenated alkyloxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy, —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —SO₂alkyl, thio and thioalkyl;

[0825] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;wherein R¹⁰⁰ is selected from: alkyl, hydroxy, aryl, alkoxy, oxo, —NH₂,—NH(alkyl) —N(alkyl)₂, ═N(OH) or —NH₂OH; provided that when L² is—OCH(R¹⁰⁰)—, R¹⁰⁰ is alkoxy, and

[0826] is phenyl, R⁵ is not —C(═O)NH—NH₂;

[0827] R¹⁰ is independently selected from the group consisting of

[0828] and —X¹-A²⁰-Y-A²¹;

[0829] wherein X¹ and Y¹ are each independently absent or selected fromthe group consisting of: —(alkyl)C(═O)N(alkyl)-, —C(═O)N(alkyl)-,—C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-,—NHC(═O)NH, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-,—OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)-, and —SO₂NH—;

[0830] A²⁰ is absent or selected from alkyl or alkenyl; and

[0831] A²¹ is selected from alkyl, alkenyl, or H;

[0832] wherein when A²⁰ or A²¹ is alkyl or alkenyl, the alkyl or alkenylmay be optionally substituted with one or more groups independentlyselected from: alkoxy, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkoxy, halogenated —SO₂alkyl, halogenated thioalkyl,hydroxy, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl,—OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio orthioalkyl;

[0833] is selected from the group consisting of aryl, cycloalkyl,partially unsaturated carbocycle, heteroaryl, heterocycloalkyl, nine toten membered benzo-fused cycloalkyl, and nine to ten memberedbenzo-fused heterocycloalkyl; wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, are optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, amino, thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy,halogenated alkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, ordialkylamino, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂;

[0834] s is an integer from 0 to 2;

[0835] m is an integer from 0 to 4; provided that when

[0836] is not substituted with Formulae A-1-a, A-1-b or A-1-c, the sumof m and s is an integer from 0 to 4, and when

[0837] is substituted with one of Formulae A-1-a, A-1-b, or A-1-c, thesum of m and s is an integer from 0 to 2;

[0838] R⁶ and R⁷ are independently selected from the group consistingof:

[0839] (a) H;

[0840] (b)

[0841] provided that R⁴ is not

[0842] (c) alkyl

[0843] (d) —C(═O)alkylOH; and

[0844] (e) —C(═O)CH₂Oalkoxy; provided that when R⁶ is present, R⁷ isabsent; and provided that when R⁷ is present, R⁶ is absent;

[0845] R⁴ is selected from the group consisting of: H and

[0846] provided that if one of R⁶ and R⁷ is

[0847] then R⁴ is H;

[0848] L³ is absent or is a linking group selected from the groupconsisting of alkyldiyl, carbonyl or —SO₂—;

[0849] is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, aralkyl, a heteroaryl, aheterocycloalkyl, a nine to ten membered benzo-fused cycloalkyl, a nineto ten membered benzo-fused heteroaryl, and a nine to ten memberedbenzo-fused heterocycloalkyl;

[0850] r is an integer from 0 to 4; and

[0851] R⁵ is independently selected from the group consisting of: alkyl,alkyl amino, alkyloxy, amino, —C(═O)NH₂, —C(═O)Oalkyl, —C(═O)OH, —CH₂OH,cyano, dialkylamino, halogen, halogenated alkyl, halogenated alkyloxy,halogenated SO₂-alkyl, halogenated thioalkyl, hydroxy, hydroxy alkyl,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —SO₂alkyl,—SO₂NH₂, thio, thioalkyl,

[0852] and —V—B¹⁰—W—B²⁰;

[0853] wherein,

[0854] V and W are each independently absent or selected from the groupconsisting of: —C(═O), —C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —N(alkyl)-,—N(alkyl)C(═O)—, —N(alkyl)C(═O)N(alkyl)-, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-,—NHC(═O)NH—, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-,—OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)- and —SO₂NH—;

[0855] B¹⁰ is absent or selected from alkyl or alkenyl;

[0856] B²⁰ is absent or selected from alkyl, alkenyl, or H;

[0857] wherein, when B¹⁰ or B²⁰ is alkyl or alkenyl, the alkyl oralkenyl group may be optionally substituted with one or more groupsindependently selected from: alkoxy, alkylamino, amino, cyano,dialkylamino, halogen, halogenated alkoxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl; and

[0858] is selected from the group consisting of: an aryl, a cycloalkyl,a partially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl,

[0859] wherein, the aryl, cycloalkyl, partially unsaturated carbocycle,heteroaryl, heterocycloalkyl, benzo-fused cycloalkyl, or benzo-fusedheterocycloalkyl, is optionally substituted with one or moresubstituents independently selected from: alkoxy, alkylamino, amino,cyano, dialkylamino, halogen, halogenated alkoxy, halogenated alkyl,halogenated —SO₂alkyl, halogenated thioalkyl, heteroaryl, hydroxy,hydroxy alkyl, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—SO₂alkyl, thio or thioalkyl;

[0860] or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof.

[0861] Further embodiments of the invention include compounds of FormulaII-GG wherein E, L², R⁴, L³ H, and (R⁵)_(r) vary as set forth in section2.a.1 above for Formula II, and R⁶ and R⁷ vary as set forth below, andcombinations of the aforementioned variations of E, L², R⁴, L³ H,(R⁵)_(r), R⁶ and R⁷.

[0862] In a preferred embodiment of the invention are compounds ofFormula II-GG, wherein R⁷ is absent, and R⁶ is selected from the groupconsisting of:

[0863] (a)

[0864] (b)

[0865] provided that R⁴ is not

[0866] (c) methyl

[0867] (d) —C(═O)CH₂OH; and

[0868] (e) —C(═O)CH₂Omethoxy;

[0869] In a preferred embodiment, the present invention is furtherdirected to compounds of Formula (II-HH):

[0870] wherein:

[0871] is selected from the group consisting of Formulae A-1, A-2 andA-3:

[0872] wherein Formula A-1 is attached on the b¹ side of Formula A-1 tothe ² ring of formula (II-HH) and optionally substituted with onesubstituent selected from the group consisting of Formulae A-1-a, A-1-band A-1-c:

[0873] wherein Formula A-1-a is attached on the a¹ side to adjacentcarbons on the d¹or d² side of Formula A-1;

[0874] wherein Formula A-1-b is attached on the a²side to adjacentcarbons on the d¹or d² side of Formula A-1; and

[0875] wherein Formula A-1-c is attached on the a⁶ side to adjacentcarbons on the d¹or d² side of Formula A-1;

[0876] wherein R⁸ is H or alkyl;

[0877] wherein Formula A-2 is attached on the b² side of Formula A-2 tothe L² ring of formula (II-HH), and A¹, A², A³, A⁴ are (i) —N—; or (ii)—C— substituted with H or alkoxy, wherein the alkoxy may be optionallyfurther substituted with alkoxy on a terminal carbon or up to 3 halogenatoms on a terminal carbon; provided that at least one and no more thantwo of A¹, A², A³, A⁴ are —N—; and

[0878] wherein Formula A-3 is attached on the b³ side of Formula A-3 tothe L² ring of formula (II-HH), and B¹, B² and B³ are independently (i)—CH— optionally substituted with alkyl, aryl, alkoxy, or halogen, (ii)—S—; (iii) —O—; or (iv) —N—; provided that no more than one of B¹, B² orB³ is —S-or —O—, and, provided that when one of B¹, B² or B³ is —S-or—O—, then the adjacent ring members are not —S-or —O—;

[0879] R⁹ is independently selected from the group consisting of:alkoxy, alkyl, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkyl, halogenated alkyloxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy, —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —SO₂alkyl, thio and thioalkyl;

[0880] L² is a linking group selected from the group consisting of:—(CH₂)—, —CH(CH₃)—, —CH(CH₂CH₃)—, and —O—, provided that when L² is —O—,neither R⁶ nor R⁷ is —CH₃;

[0881] R¹⁰ is independently selected from the group consisting of

[0882] and —X¹-A²⁰-Y¹-A²¹,

[0883] wherein X¹ and Y¹ are each independently absent or selected fromthe group consisting of: -(alkyl)C(═O)N(alkyl)-, —C(═O)N(alkyl)-,—C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-,—NHC(═O)NH, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-,—OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)-, and —SO₂NH—;

[0884] A²⁰ is absent or selected from alkyl or alkenyl; and

[0885] A²¹ is selected from alkyl, alkenyl, or H;

[0886] wherein when A²⁰ or A²¹ is alkyl or alkenyl, the alkyl or alkenylmay be optionally substituted with one or more groups independentlyselected from: alkoxy, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkoxy, halogenated —SO₂alkyl, halogenated thioalkyl,hydroxy, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl,—OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio orthioalkyl;

[0887] is selected from the group consisting of aryl, cycloalkyl,partially unsaturated carbocycle, heteroaryl, heterocycloalkyl, nine toten membered benzo-fused cycloalkyl, and nine to ten memberedbenzo-fused heterocycloalkyl; wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, are optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, amino, thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy,halogenated alkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, ordialkylamino, —NHC(═O)NH₂—NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂;

[0888] s is an integer from 0 to 2;

[0889] m is an integer from 0 to 4; provided that when

[0890] is not substituted with Formulae A-1-a, A-1-b or A-1-c, the sumof m and s is an integer from 0 to 4, and when

[0891] is substituted with one of Formulae A-1-a, A-1-b, or A-1-c, thesum of m and s is an integer from 0 to 2;

[0892] R⁶ and R⁷ are independently selected from the group consistingof:

[0893] (a)

[0894] (b)

[0895] provided that R⁴ is not

[0896] (c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —(C═O)OH, —C(═O)Oalkyl,—C(═O)Oaryl, —C(═O)Oheteroaryl, —(C═O)NH₂, —(C═O)NHalkyl,—(C═O)N(alkyl)₂, —C(═O)alkyl, -phenyl-OCH₃ or -phenyl-OC(═O)alkyl;

[0897] (d) —C(═O)(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, orbenzyl;

[0898] (e) —C(═O)CH₂O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl,or benzyl;

[0899] (f) —C(═O)alkyl, or —C(═O)(C₃₋₆)cycloalkyl, wherein said—C(═O)alkyl, and —C(═O)(C₃₋₆)cycloalkyl may be optionally substitutedwith one or more groups independently selected from: —OH, —Oalkyl,—Oalkylaryl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl,—NHC(═O)alkyl, —NHSO₂alkyl, or —OC(═O)alkyl;

[0900] (g) —C(═O)(CH₂)₁₋₃aryl, —C(═O)aryl, —C(═O)(CH₂)₁₋₃heteroaryl, or—C(═O)heteroaryl, wherein said —C(═O)(CH₂)₁₋₃aryl, —C(═O)aryl,—C(═O)(CH₂)₁₋₃heteroaryl, and —C(═O)heteroaryl may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl;

[0901] (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with methyl, ethyl, —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, or heterocycloalkyl;

[0902] (hh) —C(═O)alkylOC(═O)alkyl-terminating with —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, or heterocycloalkyl;

[0903] (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, orbenzyl;

[0904] (j) —C(═O)Oalkyl, or —C(═O)O(C₃₋₆)cycloalkyl, wherein said—C(═O)Oalkyl, and —C(═O)O(C₃₋₆)cycloalkyl may be optionally substitutedwith one or more groups independently selected from: —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl,—OC(═O)alkyl, —C(═O)OH, —C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or—C(═O)N(alkyl)₂;

[0905] (k) —C(═O)O(CH₂)₁₋₃aryl, —C(═O)Oaryl, —C(═O)O(CH₂)₁₋₃heteroaryl,or —C(═O)Oheteroaryl, wherein said —C(═O)O(CH₂)₁₋₃aryl, —C(═O)Oaryl,—C(═O)O(CH₂)₁₋₃heteroaryl, or —C(═O)Oheteroaryl may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl;

[0906] (l) —C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H, methyl, ethyl,benzyl, —CH₂CH₂NH₂, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂,—CH₂CH₂-1-pyrrolidinyl, —CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl,—CH₂CH₂-1-piperazinyl, —CH₂CH₂-1-(4-CH₃)-piperazinyl or —C(═O)alkyl;

[0907] (m) —C(═O)NH₂, —C(═O)NH(C₁₋₂₀)alkyl, —C(═O)NH(C₃₋₆)cycloalkyl, or—C(═O)N(alkyl)₂, wherein said —C(═O)NH(C₁₋₂₀)alkyl,—C(═O)NH(C₃₋₆)cycloalkyl, and —C(═O)N(alkyl)₂ may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)alkenyl, —NHC(═O)aryl, —C(═O)OH,—C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂; and, whereinthe aryl portion of said —NHC(═O)aryl may be optionally substituted withone or more groups independently selected from: alkyl, —OH, —Oalkyl,—NH₂, —NHalkyl, —N(alkyl)₂, halogen or nitrile;

[0908] (n) —C(═O)NH(CH₂)₁₋₃aryl, —C(═O)NHaryl,—C(═O)NH(CH₂)₁₋₃heteroaryl, or —C(═O)NHheteroaryl, wherein said—C(═O)NH(CH₂)₁₋₃aryl, —C(═O)NHaryl, —C(═O)NH(CH₂)₁₋₃heteroaryl, and—C(═O)NHheteroaryl may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl;

[0909] (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with H, methyl,ethyl, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃,—CH₂CH₂OC(═O)alkyl, or —C(═O)aryl; wherein the aryl portion of said—C(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile;

[0910] (p) —C(═S)NH₂;

[0911] (q) —C(═S)NHalkyl;

[0912] (r) —C(═S)N(alkyl)₂;

[0913] (s) —SO₂NH₂;

[0914] (t) —SO₂NHalkyl;

[0915] (u) —SO₂N(alkyl)₂;

[0916] (v) —P(═O)(OCH₃)₂; and

[0917] (w) —P(═O)(OCH₂CH₃)₂;

[0918] provided that when R⁶ is present, R⁷ is absent; and provided thatwhen R⁷ is present, R⁶ is absent;

[0919] R⁴ is selected from the group consisting of: H and

[0920] provided that if one of R⁶and R⁷ is

[0921] then R⁴ is H;

[0922] L³ is absent or is a linking group selected from the groupconsisting of alkyldiyl, carbonyl or —SO₂—;

[0923] is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, aralkyl, a heteroaryl, aheterocycloalkyl, a nine to ten membered benzo-fused cycloalkyl, a nineto ten membered benzo-fused heteroaryl, and a nine to ten memberedbenzo-fused heterocycloalkyl;

[0924] r is an integer from 0 to 4; and

[0925] R⁵ is independently selected from the group consisting of: alkyl,alkyl amino, alkyloxy, amino, —C(═O)NH₂, —C(═O)Oalkyl, —C(═O)OH, —CH₂OH,cyano, dialkylamino, halogen, halogenated alkyl, halogenated alkyloxy,halogenated SO₂-alkyl, halogenated thioalkyl, hydroxy, hydroxy alkyl,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —SO₂alkyl,—SO₂NH₂, thio, thioalkyl,

[0926]  and —V—B¹⁰—W—B²⁰;

[0927] wherein,

[0928] V and W are each independently absent or selected from the groupconsisting of: —C(═O), —C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —N(alkyl)-,—N(alkyl)C(═O)—, —N(alkyl)C(═O)N(alkyl)-, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-,—NHC(═O)NH—, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-,—OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)- and —SO₂NH—;

[0929] B¹⁰ is absent or selected from alkyl or alkenyl;

[0930] B²⁰ is absent or selected from alkyl, alkenyl, or H;

[0931] wherein, when B¹⁰ or B²⁰ is alkyl or alkenyl, the alkyl oralkenyl group may be optionally substituted with one or more groupsindependently selected from: alkoxy, alkylamino, amino, cyano,dialkylamino, halogen, halogenated alkoxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl; and

[0932] is selected from the group consisting of: an aryl, a cycloalkyl,a partially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl,

[0933] wherein, the aryl, cycloalkyl, partially unsaturated carbocycle,heteroaryl, heterocycloalkyl, benzo-fused cycloalkyl, or benzo-fusedheterocycloalkyl, is optionally substituted with one or moresubstituents independently selected from: alkoxy, alkylamino, amino,cyano, dialkylamino, halogen, halogenated alkoxy, halogenated alkyl,halogenated —SO₂alkyl, halogenated thioalkyl, heteroaryl, hydroxy,hydroxy alkyl, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—SO₂alkyl, thio or thioalkyl;

[0934] or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof.

[0935] Further embodiments of the invention include compounds of FormulaII-HH wherein E, R⁴, R⁶, R⁷, L³ H, and (R⁵)_(r) vary as set forth insection 2.a.1 above for Formula II, and L² varies as set forth below,and combinations of the aforementioned variations of E, L², R⁴, R⁶, R⁷,L³ H, (R⁵)_(r).

[0936] In a preferred embodiment of the invention are compounds ofFormula II-HH, wherein

[0937] L² is a linking group selected from the group consisting of:—(CH₂)—, —CH(CH₃)—, —CH(CH₂CH₃)—.

[0938] In a preferred embodiment, the present invention is furtherdirected to compounds of Formula (II-JJ):

[0939] wherein

[0940] R⁶ and R⁷ are independently selected from the group consistingof:

[0941] (a)

[0942] (b)

[0943] provided that R⁴ is not

[0944] (c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —(C═O)OH, —C(═O)Oalkyl,—C(═O)Oaryl, —C(═O)Oheteroaryl, —(C═O)NH₂, —(C═O)NHalkyl,—(C═O)N(alkyl)₂, —C(═O)alkyl, -phenyl-OCH₃ or -phenyl-OC(═O)alkyl;

[0945] (d) —C(═O)(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, orbenzyl;

[0946] (e) —C(═O)CH₂O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl,or benzyl;

[0947] (f) —C(═O)alkyl, or —C(═O)(C₃₋₆)cycloalkyl, wherein said—C(═O)alkyl, and —C(═O)(C₃₋₆)cycloalkyl may be optionally substitutedwith one or more groups independently selected from: —OH, —Oalkyl,—Oalkylaryl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl,—NHC(═O)alkyl, —NHSO₂alkyl, or —OC(═O)alkyl;

[0948] (g) —C(═O)(CH₂)₁₋₃aryl, —C(═O)aryl, —C(═O)(CH₂)₁₋₃heteroaryl, or—C(═O)heteroaryl, wherein said —C(═O)(CH₂)₁₋₃aryl, —C(═O)aryl,—C(═O)(CH₂)₁₋₃heteroaryl, and —C(═O)heteroaryl may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl;

[0949] (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with methyl, ethyl, —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, or heterocycloalkyl;

[0950] (hh) —C(═O)alkylOC(═O)alkyl-terminating with —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, or heterocycloalkyl;

[0951] (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, orbenzyl;

[0952] (j) —C(═O)Oalkyl, or —C(═O)O(C₃₋₆)cycloalkyl, wherein said—C(═O)Oalkyl, and —C(═O)O(C₃₋₆)cycloalkyl may be optionally substitutedwith one or more groups independently selected from: —OH, —Oalkyl, —NH₂,—NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl,—OC(═O)alkyl, —C(═O)OH, —C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or—C(═O)N(alkyl)₂;

[0953] (k) —C(═O)O(CH₂)₁₋₃aryl, —C(═O)Oaryl, —C(═O)O(CH₂)₁₋₃heteroaryl,or —C(═O)Oheteroaryl, wherein said —C(═O)O(CH₂)₁₋₃aryl, —C(═O)Oaryl,—C(═O)O(CH₂)₁₋₃heteroaryl, or —C(═O)Oheteroaryl may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl;

[0954] (l) —C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H, methyl, ethyl,benzyl, —CH₂CH₂NH₂, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂,—CH₂CH₂-1-pyrrolidinyl, —CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl,—CH₂CH₂-1-piperazinyl, —CH₂CH₂-1-(4-CH₃)-piperazinyl or —C(═O)alkyl;

[0955] (m) —C(═O)NH₂, —C(═O)NH(C₁₋₂₀)alkyl, —C(═O)NH(C₃₋₆)cycloalkyl, or—C(═O)N(alkyl)₂, wherein said —C(═O)NH(C₁₋₂₀)alkyl,—C(═O)NH(C₃₋₆)cycloalkyl, and —C(═O)N(alkyl)₂ may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)alkenyl, —NHC(═O)aryl, —C(═O)OH,—C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂; and, whereinthe aryl portion of said —NHC(═O)aryl may be optionally substituted withone or more groups independently selected from: alkyl, —OH, —Oalkyl,—NH₂, —NHalkyl, —N(alkyl)₂, halogen or nitrile;

[0956] (n) —C(═O)NH(CH₂)₁₋₃aryl, —C(═O)NHaryl,—C(═O)NH(CH₂)₁₋₃heteroaryl, or —C(═O)NHheteroaryl, wherein said—C(═O)NH(CH₂)₁₋₃aryl, —C(═O)NHaryl, —C(═O)NH(CH₂)₁₋₃heteroaryl, and—C(═O)NHheteroaryl may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl;

[0957] (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with H, methyl,ethyl, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃,—CH₂CH₂OC(═O)alkyl, or —C(═O)aryl; wherein the aryl portion of said—C(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile;

[0958] (p) —C(═S)NH₂;

[0959] (q) —C(═S)NHalkyl;

[0960] (r) —C(═S)N(alkyl)₂;

[0961] (s) —SO₂NH₂;

[0962] (t) —SO₂NHalkyl;

[0963] (u) —SO₂N(alkyl)₂;

[0964] (v) —P(═O)(OCH₃)₂; and

[0965] (w) —P(═O)(OCH₂CH₃)₂;

[0966] provided that when R⁶ is present, R⁷ is absent; and provided thatwhen R⁷ is present, R⁶ is absent;

[0967] R⁴ is selected from the group consisting of: H and

[0968] provided that if one of R⁶and R⁷ is

[0969] then R⁴ is H; or an optical isomer, enantiomer, diastereomer,racemate, or pharmaceutically acceptable salt thereof.

[0970] Further embodiments of the invention include compounds of FormulaII-JJ wherein R⁶ and R⁷ vary as set forth in section 2.a.1 above forFormula II.

[0971] 2.c Preferred Compounds

[0972] In a preferred embodiment, the present invention is furtherdirected to a compound selected from the group consisting of:

[0973] In a preferred embodiment, the present invention is furtherdirected to a compound selected from the group consisting of:

[0974] In a preferred embodiment, the present invention is furtherdirected to a compound of the following formula:

[0975] In a preferred embodiment, the present invention is furtherdirected to a compound of the following formula:

[0976] In a preferred embodiment, the present invention is furtherdirected to a compound of the following formula:

[0977] In a preferred embodiment, the present invention is furtherdirected to a compound of the following formula:

[0978] 2.d. Preparation of Compounds of Formula (IIa)

[0979] The present invention is further directed to a process for thepreparation of compounds of Formula (IIa):

[0980] wherein:

[0981] is selected from the group consisting of Formulae A-1, A-2 andA-3:

[0982] wherein Formula A-1 is attached on the b¹ side of Formula A-1 tothe L² ring of formula (II) and optionally substituted with onesubstituent selected from the group consisting of Formulae A-1-a, A-1-band A-1-c:

[0983] wherein Formula A-1-a is attached on the a¹ side to adjacentcarbons on the d¹or d² side of Formula A-1;

[0984] wherein Formula A-1-b is attached on the a²side to adjacentcarbons on the d¹or d² side of Formula A-1; and

[0985] wherein Formula A-1-c is attached on the a⁶ side to adjacentcarbons on the d¹or d² side of Formula A-1;

[0986] wherein R⁸ is H or alkyl;

[0987] wherein Formula A-2 is attached on the b² side of Formula A-2 tothe L² ring of formula (II), and A¹, A², A³, A⁴are (i) —N—; or (ii) —C—substituted with H or alkoxy, wherein the alkoxy may be optionallyfurther substituted with alkoxy on a terminal carbon or up to 3 halogenatoms on a terminal carbon; provided that at least one and no more thantwo of A¹, A², A³, A⁴ are —N—; and

[0988] wherein Formula A-3 is attached on the b³ side of Formula A-3 tothe L² ring of formula (II), and B¹, B² and B³ are independently (i)—CH— optionally substituted with C₁₋₄alkyl, aryl, alkoxy, or halogen,(ii) —S—; (iii) —O—; or (iv) —N—; provided that no more than one of B¹,B² or B³ is —S-or —O—, and, provided that when one of B¹, B² or B³ is—S-or —O—, then the adjacent ring members are not —S-or —O—;

[0989] R⁹ is independently selected from the group consisting of:alkoxy, alkyl, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkyl, halogenated alkyloxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy, —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —SO₂alkyl, thio and thioalkyl;

[0990] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;wherein R¹⁰⁰ is selected from: alkyl, hydroxy, aryl, alkoxy, oxo, —NH₂,—NH(alkyl) —N(alkyl)₂, ═N(OH) or —NH₂OH; provided that when L² is—OCH(R¹⁰⁰)—, R¹⁰⁰ is alkoxy, and

[0991] is phenyl, R⁵ is not —C(═O)NH—NH₂;

[0992] R¹⁰ is independently selected from the group consisting of

[0993] and —X¹-A²⁰-Y¹-A²¹;

[0994] wherein X¹ and Y¹ are each independently absent or selected fromthe group consisting of: —(alkyl)C(═O)N(alkyl)-, —C(═O)N(alkyl)-,—C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-,—NHC(═O)NH, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-,—OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)-, and —SO₂NH—;

[0995] A²⁰ is absent or selected from alkyl or alkenyl; and

[0996] A²¹ is selected from alkyl, alkenyl, or H;

[0997] wherein when A²⁰ or A²¹ is alkyl or alkenyl, the alkyl or alkenylmay be optionally substituted with one or more groups independentlyselected from: alkoxy, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkoxy, halogenated —SO₂alkyl, halogenated thioalkyl,hydroxy, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl,—OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio orthioalkyl;

[0998] is selected from the group consisting of aryl, cycloalkyl,partially unsaturated carbocycle, heteroaryl, heterocycloalkyl, nine toten membered benzo-fused cycloalkyl, and nine to ten memberedbenzo-fused heterocycloalkyl; wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, are optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, amino, thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy,halogenated alkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, ordialkylamino, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂;

[0999] s is an integer from 0 to 2;

[1000] m is an integer from 0 to 4; provided that when

[1001] is not substituted with Formulae A-1-a, A-1-b or A-1-c, the sumof m and s is an integer from 0 to 4, and when

[1002] is substituted with one of Formulae A-1-a, A-1-b, or A-1-c, thesum of m and s is an integer from 0 to 2;

[1003] L³ is absent or is a linking group selected from the groupconsisting of alkyldiyl, carbonyl or —SO₂—;

[1004] is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, aralkyl, a heteroaryl, aheterocycloalkyl, a nine to ten membered benzo-fused cycloalkyl, a nineto ten membered benzo-fused heteroaryl, and a nine to ten memberedbenzo-fused heterocycloalkyl;

[1005] r is an integer from 0 to 4; and

[1006] R⁵ is independently selected from the group consisting of: alkyl,alkyl amino, alkyloxy, amino, —C(═O)NH₂, —C(═O)Oalkyl, —C(═O)OH, —CH₂OH,cyano, dialkylamino, halogen, halogenated alkyl, halogenated alkyloxy,halogenated SO₂-alkyl, halogenated thioalkyl, hydroxy, hydroxy alkyl,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —SO₂alkyl,—SO₂NH₂, thio, thioalkyl,

[1007] and —V—B¹⁰—W—B²⁰;

[1008] wherein,

[1009] V and W are each independently absent or selected from the groupconsisting of: —C(═O), —C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —N(alkyl)-,—N(alkyl)C(═O)—, —N(alkyl)C(═O)N(alkyl)-, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-,—NHC(═O)NH—, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-,—OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)- and —SO₂NH—;

[1010] B¹⁰ is absent or selected from alkyl or alkenyl;

[1011] B²⁰ is absent or selected from alkyl, alkenyl, or H;

[1012] wherein, when B¹⁰ or B²⁰ is alkyl or alkenyl, the alkyl oralkenyl group may be optionally substituted with one or more groupsindependently selected from: alkoxy, alkylamino, amino, cyano,dialkylamino, halogen, halogenated alkoxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl; and

[1013] is selected from the group consisting of: an aryl, a cycloalkyl,a partially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl,

[1014] wherein, the aryl, cycloalkyl, partially unsaturated carbocycle,heteroaryl, heterocycloalkyl, benzo-fused cycloalkyl, or benzo-fusedheterocycloalkyl, is optionally substituted with one or moresubstituents independently selected from: alkoxy, alkylamino, amino,cyano, dialkylamino, halogen, halogenated alkoxy, halogenated alkyl,halogenated —SO₂alkyl, halogenated thioalkyl, heteroaryl, hydroxy,hydroxy alkyl, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—SO₂alkyl, thio or thioalkyl;

[1015] or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof;

[1016] comprising

[1017] reacting a compound of formula (T1) with1,1′-thiocarbonyldiimidazole, in the presence of a base, in an aproticsolvent, to yield the corresponding compound of formula (T5);

[1018] reacting a compound of formula (T5) with a compound of formula(T6), in an aprotic solvent, to yield the corresponding compound offormula (T3);

[1019] reacting a compound of formula (T3) with hydrazine,

[1020] to yield the corresponding compound of formula (IIa).

[1021] The present invention is further directed to a process for thepreparation of compounds of formula (T5)

[1022] wherein:

[1023] is selected from the group consisting of Formulae A-1, A-2 andA-3:

[1024] wherein Formula A-1 is attached on the b¹ side of Formula A-1 tothe L² ring of formula (II) and optionally substituted with onesubstituent selected from the group consisting of Formulae A-1-a, A-1-band A-1-c:

[1025] wherein Formula A-1-a is attached on the a¹ side to adjacentcarbons on the d¹or d² side of Formula A-1;

[1026] wherein Formula A-1-b is attached on the a²side to adjacentcarbons on the d¹or d² side of Formula A-1; and

[1027] wherein Formula A-1-c is attached on the a⁶ side to adjacentcarbons on the d¹or d² side of Formula A-1;

[1028] wherein R⁸ is H or alkyl;

[1029] wherein Formula A-2 is attached on the b² side of Formula A-2 tothe L² ring of formula (II), and A¹, A², A³, A⁴ are (i) —N—; or (ii) —C—substituted with H or alkoxy, wherein the alkoxy may be optionallyfurther substituted with alkoxy on a terminal carbon or up to 3 halogenatoms on a terminal carbon; provided that at least one and no more thantwo of A¹, A², A³, A⁴ are —N—; and

[1030] wherein Formula A-3 is attached on the b³ side of Formula A-3 tothe L² ring of formula (II), and B¹, B² and B³ are independently (i)—CH— optionally substituted with alkyl, aryl, alkoxy, or halogen, (ii)—S—; (iii) —O—; or (iv) —N—; provided that no more than one of B¹, B² orB³ is —S-or —O—, and, provided that when one of B¹, B² or B³ is —S-or—O—, then the adjacent ring members are not —S-or —O—;

[1031] R⁹ is independently selected from the group consisting of:alkoxy, alkyl, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkyl, halogenated alkyloxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy, —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —SO₂alkyl, thio and thioalkyl;

[1032] L² is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;wherein R¹⁰⁰ is selected from: alkyl, hydroxy, aryl, alkoxy, oxo, —NH₂,—NH(alkyl) —N(alkyl)₂, ═N(OH) or —NH₂OH;

[1033] R¹⁰ is independently selected from the group consisting of

[1034] and —X¹-A²⁰-Y¹-A²¹;

[1035] wherein X¹ and Y¹ are each independently absent or selected fromthe group consisting of: -(alkyl)C(═O)N(alkyl)-, —C(═O)N(alkyl)-,—C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-,—NHC(═O)NH, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-,—OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)-, and —SO₂NH—;

[1036] A²⁰ is absent or selected from alkyl or alkenyl; and

[1037] A²¹ is selected from alkyl, alkenyl, or H;

[1038] wherein when A²⁰ or A²¹ is alkyl or alkenyl, the alkyl or alkenylmay be optionally substituted with one or more groups independentlyselected from: alkoxy, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkoxy, halogenated —SO₂alkyl, halogenated thioalkyl,hydroxy, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl,—OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio orthioalkyl;

[1039] is selected from the group consisting of aryl, cycloalkyl,partially unsaturated carbocycle, heteroaryl, heterocycloalkyl, nine toten membered benzo-fused cycloalkyl, and nine to ten memberedbenzo-fused heterocycloalkyl; wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, are optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, amino, thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy,halogenated alkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, ordialkylamino, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂;

[1040] s is an integer from 0 to 2;

[1041] m is an integer from 0 to 4; provided that when

[1042] is not substituted with Formulae A-1-a, A-1-b or A-1-c, the sumof m and s is an integer from 0 to 4, and when

[1043] is substituted with one of Formulae A-1-a, A-1-b, or A-1-c, thesum of m and s is an integer from 0 to 2;

[1044] or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof;

[1045] comprising

[1046] reacting a compound of formula (T1) with1,1′-thiocarbonyldiimidazole, in the presence of a base, in an aproticsolvent, to yield the corresponding compound of formula (T5).

[1047] The present invention is further directed to a process for thepreparation of compounds of formula (T3)

[1048] wherein:

[1049] is selected from the group consisting of Formulae A-1, A-2 andA-3:

[1050] wherein Formula A-1 is attached on the b¹ side of Formula A-1 tothe L² ring of formula (II) and optionally substituted with onesubstituent selected from the group consisting of Formulae A-1-a, A-1-band A-1-c:

[1051] wherein Formula A-1-a is attached on the a¹ side to adjacentcarbons on the d¹or d² side of Formula A-1;

[1052] wherein Formula A-1-b is attached on the a²side to adjacentcarbons on the d¹or d² side of Formula A-1; and

[1053] wherein Formula A-1-c is attached on the a⁶ side to adjacentcarbons on the d¹or d² side of Formula A-1;

[1054] wherein R⁸ is H or alkyl;

[1055] wherein Formula A-2 is attached on the b² side of Formula A-2 tothe L² ring of formula (II), and A¹, A², A³, A⁴ are (i) —N—; or (ii) —C—substituted with H or alkoxy, wherein the alkoxy may be optionallyfurther substituted with alkoxy on a terminal carbon or up to 3 halogenatoms on a terminal carbon; provided that at least one and no more thantwo of A¹, A², A³, A⁴ are —N—; and

[1056] wherein Formula A-3 is attached on the b³ side of Formula A-3 tothe L² ring of formula (II), and B¹, B² and B³are independently (i) —CH—optionally substituted with alkyl, aryl, alkoxy, or halogen, (ii) —S—;(iii) —O—; or (iv) —N—; provided that no more than one of B¹, B² or B³is —S-or —O—, and, provided that when one of B¹, B² or B³ is —S-or —O—,then the adjacent ring members are not —S-or —O—;

[1057] R⁹ is independently selected from the group consisting of:alkoxy, alkyl, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkyl, halogenated alkyloxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy, —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —SO₂alkyl, thio and thioalkyl;

[1058] L2 is a linking group selected from the group consisting of:—(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;wherein R¹⁰⁰ is selected from: alkyl, hydroxy, aryl, alkoxy, oxo, —NH₂,—NH(alkyl) —N(alkyl)₂, ═N(OH) or —NH20H; provided that when L² is—OCH(R¹⁰⁰)—, R¹⁰⁰ is alkoxy, and

[1059] phenyl, R⁵ is not —C(═O)NH—NH₂;

[1060] R¹⁰ is independently selected from the group consisting of

[1061] and —X¹-A²⁰-Y¹-A²¹;

[1062] wherein X¹ and Y¹ are each independently absent or selected fromthe group consisting of: -(alkyl)C(═O)N(alkyl)-, —C(═O)N(alkyl)-,—C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-,—NHC(═O)NH, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-,—OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)-, and —SO₂NH—;

[1063] A²⁰ is absent or selected from alkyl or alkenyl; and

[1064] A²¹ is selected from alkyl, alkenyl, or H;

[1065] wherein when A²⁰ or A²¹ is alkyl or alkenyl, the alkyl or alkenylmay be optionally substituted with one or more groups independentlyselected from: alkoxy, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkoxy, halogenated —SO₂alkyl, halogenated thioalkyl,hydroxy, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl;

[1066] is selected from the group consisting of aryl, cycloalkyl,partially unsaturated carbocycle, heteroaryl, heterocycloalkyl, nine toten membered benzo-fused cycloalkyl, and nine to ten memberedbenzo-fused heterocycloalkyl; wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, are optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, amino, thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy,halogenated alkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, ordialkylamino, —NHC(—O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂;

[1067] s is an integer from 0 to 2;

[1068] m is an integer from 0 to 4; provided that when

[1069] is not substituted with Formulae A-1-a, A-1-b or A-1-c, the sumof m and s is an integer from 0 to 4, and when

[1070] is substituted with one of Formulae A-1-a, A-1-b, or A-1-c, thesum of m and s is an integer from 0 to 2;

[1071] L³ is absent or is a linking group selected from the groupconsisting of alkyldiyl, carbonyl or —SO₂—;

[1072] is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, aralkyl, a heteroaryl, aheterocycloalkyl, a nine to ten membered benzo-fused cycloalkyl, a nineto ten membered benzo-fused heteroaryl, and a nine to ten memberedbenzo-fused heterocycloalkyl;

[1073] r is an integer from 0 to 4; and

[1074] R⁵ is independently selected from the group consisting of: alkyl,alkyl amino, alkyloxy, amino, —C(═O)NH₂, —C(═O)Oalkyl, —C(═O)OH, —CH₂OH,cyano, dialkylamino, halogen, halogenated alkyl, halogenated alkyloxy,halogenated SO₂-alkyl, halogenated thioalkyl, hydroxy, hydroxy alkyl,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —SO₂alkyl,—SO₂NH₂, thio, thioalkyl,

[1075] and —V—B¹⁰—W—B²⁰;

[1076] wherein,

[1077] V and W are each independently absent or selected from the groupconsisting of: —C(═O), —C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —N(alkyl)-,—N(alkyl)C(═O)—, —N(alkyl)C(═O)N(alkyl)-, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-,—NHC(═O)NH—, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-,—OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)- and —SO₂NH—;

[1078] B¹⁰ is absent or selected from alkyl or alkenyl;

[1079] B²⁰ is absent or selected from alkyl, alkenyl, or H;

[1080] wherein, when B¹⁰ or B²⁰ is alkyl or alkenyl, the alkyl oralkenyl group may be optionally substituted with one or more groupsindependently selected from: alkoxy, alkylamino, amino, cyano,dialkylamino, halogen, halogenated alkoxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl; and

[1081] is selected from the group consisting of: an aryl, a cycloalkyl,a partially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl,

[1082] wherein, the aryl, cycloalkyl, partially unsaturated carbocycle,heteroaryl, heterocycloalkyl, benzo-fused cycloalkyl, or benzo-fusedheterocycloalkyl, is optionally substituted with one or moresubstituents independently selected from: alkoxy, alkylamino, amino,cyano, dialkylamino, halogen, halogenated alkoxy, halogenated alkyl,halogenated —SO₂alkyl, halogenated thioalkyl, heteroaryl, hydroxy,hydroxy alkyl, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—SO₂alkyl, thio or thioalkyl;

[1083] or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof;

[1084] comprising

[1085] reacting a compound of formula (T5) with a compound of formula(T6), in an aprotic solvent, to yield the corresponding compound offormula (T3).

[1086] Representative Compounds

[1087] In an embodiment of the present invention are compounds as listedin Tables 1 through 13; below. Molecular weight indicated by “MS,”expressed in m/z (M+H)⁺ units. Compounds which have been synthesized areas listed in Tables 1 through 5 and 7 through 13.

[1088] (In reference to compounds of formulae (I) and (II), G represents

[1089] in Formula (I) and

[1090] in Formula (II); R^(A), R^(B), R^(C) and R^(D) represent an R² orR³ group in Formula (I), and/or an R⁹ or R¹⁰ group in Formula (II).Additional representative examples of compounds within the scope of theinvention, are listed in Table 6.

[1091] In Tables 4 and 6 below, the

[1092] ring (the A/E ring,), representing the

[1093] (A ring) in Formula (I) and the

[1094] (E ring) in Formula (II) are numbered based on convention,counting clockwise, unless otherwise indicated by convention, with theleading numbers indicating the carbon atoms bound to the rest of thecore molecule. Thus, for example, for in the structure below

[1095] the A/E ring, substituent would be named4,5-(3-methyl-isoxazolyl).

[1096] Named A/E ring, substituents followed by an * are numberedcounterclockwise, following convention. For example, in the structurebelow

[1097] the A/E ring, substituent would be named5,6-(2-methyl-8-ethoxy-benzoxazolyl)*.

[1098] Otherwise, when the A/E ring, is a phenyl, the phenyl group, bydefinition, is bound at the 1,2 positions, and the phenyl ringsubstituents are numbered counting clockwise, as in the first structure(4,5-isoxazolyl) shown above. TABLE 1

Cpd G R^(A) MS 8 phenyl methyl 278 23 phenyl methyl 262 71 phenyl3-(N,N-dimethyl-amino)- 349 propoxy 72 3-chloro-phenyl3-(N,N-dimethyl-amino)- 383 propoxy 73 4-fluoro-phenyl3-(N,N-dimethyl-amino)- 367 propoxy 74 3-methoxy-phenyl3-(N,N-dimethyl-amino)- 379 propoxy 75 3-pyridyl 3-(N,N-dimethyl-amino)-350 propoxy 77 3-(methoxy-carbonyl)- 3-(N,N-dimethyl-amino)- 407 phenylpropoxy 90 3-fluoro-phenyl 3-(N,N-dimethyl-amino)- 367 propoxy 984-fluoro-phenyl methyl 280 99 3-fluoro-phenyl methyl 280 100 3-pyridylmethyl 263 101 2,5-dimethoxy-phenyl methyl 322 102 2,4-dimethoxy-phenylmethyl 322 103 2,5-difluoro-phenyl methyl 298 104 4-trifluoromethoxy-methyl 346 phenyl 105 4-trifluoromethyl- methyl 330 phenyl 1444-fluoro-phenyl methoxy 296 145 4-methoxy-phenyl methoxy 308 1463-pyridyl methoxy 279 147 2,5-dimethoxy-phenyl methoxy 338 1482,4-dimethoxy-phenyl methoxy 338 149 3-trifluoromethoxy- methoxy 362phenyl 150 3-trifluoromethyl- methoxy 346 phenyl 392 3-chloro-phenyl3-morpholin-4-yl-propoxy 425 393 3-fluoro-phenyl3-morpholin-4-yl-propoxy 409 394 3-ethoxy-phenyl3-morpholin-4-yl-propoxy 435 414 2,6-difluoro-benzyl3-morpholin-4-yl-propoxy 441 415 2,6-dichloro-benzyl3-morpholin-4-yl-propoxy 474 416 2-fluoro-benzyl3-morpholin-4-yl-propoxy 423 417 3-methoxy-5- methoxy 376trifluoromethyl-phenyl 418 3-(amino-sulfonyl)- methoxy 357 phenyl 4223-fluoro-phenyl methoxy 296 423 2,6-difluoro-benzyl methoxy 328 4403-chloro-phenyl 3-hydroxy-propoxy 356 441 3-ethoxy-phenyl3-hydroxy-propoxy 366 442 3-fluoro-phenyl 3-hydroxy-propoxy 340 4432,6-difluoro-benzyl 3-hydroxy-propoxy 372 444 2-fluoro-benzyl3-hydroxy-propoxy 354 445 2-methyl-benzyl 3-hydroxy-propoxy 350 4683-bromo-phenyl 2,3-dihydroxy-propoxy 417 469 3-fluoro-phenyl2,3-dihydroxy-propoxy 356 478 3-bromo-phenyl 2-(pyrrolidin-1-yl)-ethoxy440 479 2,6-difluoro-benzyl 2,3-dihydroxy-propoxy 421

[1099] TABLE 2

Cpd G R^(B) R^(C) MS 1 phenyl H H 248 2 phenyl methoxy ethoxy 308 34-chloro-phenyl H H 282 4 3-chloro-phenyl methoxy methoxy 342 54-chloro-phenyl methoxy methoxy 342 6 4-methoxy-phenyl methoxy methoxy338 7 phenyl methoxy H 278 9 2-chloro-phenyl methoxy methoxy 342 104-(ethoxy-carbonyl)- methoxy methoxy 380 phenyl 11 3-(methoxy- methoxymethoxy 366 carbonyl)-phenyl 12 2-fluoro-phenyl methoxy methoxy 326 134-fluoro-phenyl methoxy methoxy 326 14 3-fluoro-phenyl methoxy methoxy326 15 2-trifluoromethoxy- methoxy methoxy 392 phenyl 164-trifluoromethoxy- methoxy methoxy 392 phenyl 17 2,4-dichloro-phenylmethoxy methoxy 377 18 3,4-dichloro-phenyl methoxy methoxy 377 193,5-dichloro-phenyl methoxy methoxy 377 20 2,3-dichloro-phenyl methoxymethoxy 377 21 phenyl chloro H 282 22 phenyl H methyl 262 24 phenylfluoro H 266 25 4-trifluoromethyl- methoxy methoxy 376 phenyl 263-trifluoromethyl- methoxy methoxy 376 phenyl 27 2-methoxy-phenylmethoxy methoxy 338 28 2-trifluoromethyl- methoxy methoxy 376 phenyl 293-methoxy-phenyl methoxy methoxy 338 30 3-pyridyl methoxy methoxy 309 312-methyl-phenyl methoxy methoxy 322 32 3-methyl-phenyl methoxy methoxy322 33 4-methyl-phenyl methoxy methoxy 322 34 2,5-dichloro-phenylmethoxy methoxy 377 36 3-hydroxy-methyl- methoxy methoxy 338 phenyl 376-indazolyl methoxy methoxy 348 38 3-hydroxy-phenyl methoxy methoxy 32439 phenyl H methoxy 278 40 4-(N,N-dimethyl- methoxy methoxy 351amino)-phenyl 41 3,5-dimethoxy- methoxy methoxy 368 phenyl 423,4,5-trimethoxy- methoxy methoxy 398 phenyl 43 2-bromo-phenyl methoxymethoxy 387 44 3-bromo-phenyl methoxy methoxy 387 45 4-bromo-phenylmethoxy methoxy 387 46 5-chloro-2-methyl- methoxy methoxy 356 phenyl 472,4-dimethoxy- methoxy methoxy 386 phenyl 48 2,5-dimethoxy- methoxymethoxy 368 phenyl 49 3,4-dimethoxy- methoxy methoxy 368 phenyl 514-(4-methyl- methoxy methoxy 406 piperazin-1-yl)- phenyl 533-chloro-4-fluoro- methoxy methoxy 360 phenyl 54 3-benzyloxy-phenylmethoxy methoxy 414 55 2,5-difluoro-phenyl methoxy methoxy 344 565-chloro-2-methoxy- methoxy methoxy 372 phenyl 57 2-isopropyl-phenylmethoxy methoxy 350 58 2-ethyl-phenyl methoxy methoxy 336 594-cyano-phenyl methoxy methoxy 333 61 3-cyano-phenyl methoxy methoxy 33362 3,4-methylenedioxy- methoxy methoxy 352 phenyl 64 phenyl 4-methyl- H346 piperazin-1-yl 65 phenyl 1-piperidinyl H 331 66 phenyl amino H 26367 cyclohexyl methoxy methoxy 314 70 3,5- methoxy methoxy 444di(trifluoromethyl) phenyl 76 2-trifluoromethyl-4- methoxy methoxy 455bromo-phenyl 78 2-furyl methoxy methoxy 298 79 5-indanyl methoxy methoxy348 81 2-(piperidin-1-yl)- methoxy methoxy 343 ethyl 82 4-fluoro-phenylmethoxy H 296 83 3-bromo-phenyl methoxy H 357 84 3-pyridyl methoxy H 27985 2,5-dimethoxy- methoxy H 338 phenyl 86 3,4-dimethoxy- methoxy H 338phenyl 87 2,5-difluoro-phenyl methoxy H 314 88 4-trifluoromethoxy-methoxy H 362 phenyl 89 4-trifluoromethyl- methoxy H 346 phenyl 92phenyl N,N-dimethyl- H 291 amino 115 3-carboxy-phenyl methoxy methoxy352 116 3-(amino-carbonyl)- methoxy methoxy 351 phenyl 1173-bromo-phenyl amino H 342 118 3-methoxy-phenyl amino H 293 1193-chloro-phenyl amino H 297 120 3-(methoxy- amino H 321 carbonyl)-phenyl121 3-fluoro-phenyl amino H 281 122 3-bromo-phenyl 4-methyl- H 425piperazin-1-yl 123 3-methoxy-phenyl 4-methyl- H 376 piperazin-1-yl 1243-chloro-phenyl 4-methyl- H 380 piperazin-1-yl 125 3-bromo-phenylhydroxy hydroxy 359 129 3-pyridyl 3-morpholin-4-yl- methoxy 422 propoxy130 3-bromo-phenyl 3-morpholin-4-yl- methoxy 500 propoxy 1313-methoxy-phenyl 3-morpholin-4-yl- methoxy 451 propoxy 1323-chloro-phenyl 3-morpholin-4-yl- methoxy 455 propoxy 133 3-(methoxy-3-morpholin-4-yl- methoxy 479 carbonyl)-phenyl propoxy 1343-fluoro-phenyl 3-morpholin-4-yl- methoxy 439 propoxy 1353-chloro-phenyl 3-methoxy- H 370 propoxy 136 3-fluoro-phenyl 3-methoxy-H 354 propoxy 137 3-(methoxy- 3-methoxy- H 394 carbonyl)-phenyl propoxy138 3-fluoro-phenyl 3-methoxy- H 354 propoxy 139 3-methoxy-phenyl3-methoxy- H 366 propoxy 140 phenyl 3-methoxy- H 336 propoxy 1413-bromo-phenyl 3-methoxy- H 415 propoxy 142 3-pyridyl 3-methoxy- H 337propoxy 143 4-methoxy-phenyl 3-methoxy- H 366 propoxy 1513-fluoro-phenyl bromo H 345 152 3-pyridyl bromo H 328 1532,5-difluoro-phenyl bromo H 363 154 3-trifluoromethoxy- bromo H 411phenyl 155 3-trifluoromethyl- bromo H 395 phenyl 156 3-methoxy-phenyl3-pyrrolidin-1-yl- methoxy 435 propoxy 157 3-(methoxy-3-pyrrolidin-1-yl- methoxy 463 carbonyl)-phenyl propoxy 158 phenyl bromoH 327 159 4-fluoro-phenyl 3-(N,N-dimethyl- H 367 amino)-propoxy 1603-fluoro-phenyl 3-(N,N-dimethyl- H 367 amino)-propoxy 161 3-pyridyl3-(N,N-dimethyl- H 350 amino)-propoxy 162 2,5-dimethoxy-3-(N,N-dimethyl- H 409 phenyl amino)-propoxy 163 2,5-difluoro-phenyl3-(N,N-dimethyl- H 385 amino)-propoxy 165 3-trifluoromethyl-3-(N,N-dimethyl- H 417 phenyl amino)-propoxy 166 3-chloro-4-fluoro-3-methoxy- methoxy 418 phenyl propoxy 167 3-chloro-4-fluoro- isopropoxyisopropoxy 416 phenyl 168 3-methoxy-phenyl isopropoxy isopropoxy 394 1693-fluoro-phenyl isopropoxy isopropoxy 382 170 4-fluoro-phenyl H methoxy296 171 4-methoxy-phenyl H methoxy 308 172 3-fluoro-phenyl H methoxy 296173 3-pyridyl H methoxy 279 174 2,5-dimethoxy- H methoxy 338 phenyl 1752,4-dimethoxy- H methoxy 338 phenyl 176 2,5-difluoro-phenyl H methoxy314 177 4-trifluoromethoxy- H methoxy 362 phenyl 178 4-trifluoromethyl-H methoxy 346 phenyl 179 3-chloro-4-fluoro- 3-morpholin-4-yl- methoxy473 phenyl propoxy 180 3-fluoro-phenyl 3-pyrroiidin-1-yl- methoxy 423propoxy 181 3-chloro-4-fluoro- 3-pyrrolidin-1-yl- methoxy 457 phenylpropoxy 182 3-fluoro-phenyl H methyl 280 183 4-methoxy-phenyl H methyl292 184 2,5-dimethoxy- H methyl 322 phenyl 185 2,5-difluoro-phenyl Hmethyl 298 186 4-trifluoromethoxy- H methyl 346 phenyl 1873-trifluoromethyl- H methyl 330 phenyl 188 3-pyridyl chloro H 283 1894-methoxy-phenyl chloro H 312 190 3-methoxy-phenyl chloro H 312 1913-fluoro-phenyl chloro H 300 192 2,5-difluoro-phenyl chloro H 318 1934-trifluoromethyl- chloro H 350 phenyl 194 4-trifluoromethoxy- chloro H366 phenyl 195 3,5- chloro H 418 di(trifluoromethyl)- phenyl 1964-dimethylamino- chloro H 325 phenyl 197 3-methyl-phenyl chloro H 296198 4-methyl-phenyl chloro H 296 199 3-fluoro-phenyl 3-(N,N-dimethyl-methoxy 397 amino)-propoxy 200 3-chloro-4-fluoro- 3-(N,N-dimethyl-methoxy 431 phenyl amino)-propoxy 201 4-fluoro-phenyl fluoro H 284 2023-chloro-4-fluoro- fluoro H 318 phenyl 203 2,5-dimethoxy- fluoro H 326phenyl 204 3,5-dimethoxy- fluoro H 326 phenyl 205 3,4-dimethoxy- fluoroH 326 phenyl 206 3,5-dimethyl-phenyl methoxy methoxy 336 2073,5-difluoro-phenyl methoxy methoxy 344 208 3-methylthio-phenyl methoxymethoxy 354 209 3-ethyl-phenyl methoxy methoxy 336 2103-(ethoxy-carbonyl)- methoxy methoxy 380 phenyl 211 3-(trifluoromethyl-methoxy methoxy 408 thio)-phenyl 212 4-fluoro-3- methoxy methoxy 394trifluoromethyl- phenyl 213 3-chloro-phenyl 3-(4-methyl- methoxy 468piperazin-1-yl)- propoxy 214 3-chloro-4-fluoro- 3-(4-methyl- methoxy 486phenyl piperazin-1-yl)- propoxy 215 3-methoxy-phenyl 3-(4-methyl-methoxy 464 piperazin-1-yl) propoxy 216 3-fluoro-phenyl 3-(4-methyl-methoxy 452 piperazin-1-yl)- propoxy 217 4-trifluoromethoxy-3-(N,N-dimethyl- H 433 phenyl amino)-propoxy 218 4-benzyloxy-phenylmethoxy methoxy 414 221 4-(piperidin-4-yl- methoxy methoxy 455sulfonyl)-phenyl 226 3-fluoro-phenyl 3-imidazol-1-yl- methoxy 420propoxy 227 3-chloro-4-fluoro- 3-imidazol-1-yl- methoxy 454 phenylpropoxy 233 4-methoxy-phenyl fluoro H 296 234 3-methoxy-phenyl fluoro H296 235 3-fluoro-phenyl fluoro H 284 236 2,5-difluoro-phenyl fluoro H302 237 4-trifluoromethyl- fluoro H 334 phenyl 238 4-trifluoromethoxy-fluoro H 350 phenyl 239 3,5- fluoro H 402 di(trifluoromethyl)- phenyl240 3-methyl-phenyl fluoro H 280 242 3-fluoro-phenyl 3-methoxy- methoxy384 propoxy 244 3-methoxy-phenyl 3-methoxy- methoxy 396 propoxy 2453-methoxy-phenyl ethoxy ethoxy 366 246 3-chloro-4-fluoro- ethoxy ethoxy388 phenyl 259 3-chloro-phenyl 2,3-dihydroxy- methoxy 402 propoxy 2603-methoxy-phenyl 2,3-dihydroxy- methoxy 398 propoxy 2613-chloro-4-fluoro- 2,3-dihydroxy- methoxy 420 phenyl propoxy 2623-fluoro-phenyl 2,3-dihydroxy- methoxy 386 propoxy 263 3-pyridyl2,3-dihydroxy- methoxy 369 propoxy 265 3-fluoro-phenyl 3-hydroxy-methoxy 370 propoxy 266 3-methoxy-phenyl 3-hydroxy- methoxy 382 propoxy267 3-chloro-4-fluoro- 3-hydroxy- methoxy 404 phenyl propoxy 2683-chloro-phenyl 3-hydroxy- methoxy 386 propoxy 269 3-fluoro-phenyl2-hydroxy-3- methoxy 439 pyrrolidin-1-yl- propoxy 270 3-methoxy-phenyl2-hydroxy-3- methoxy 451 pyrrolidin-1-yl- propoxy 276 4-fluoro-3-nitro-methoxy methoxy 371 phenyl 277 3-chloro-4-methoxy- methoxy methoxy 372phenyl 278 3-(1-hydroxy-ethyl)- methoxy methoxy 352 phenyl 2793,5-di(tert-butyl)- methoxy methoxy 420 phenyl 280 3-chloro-4-fluoro-2-hydroxy-3- methoxy 473 phenyl pyrrolidin-1-yl- propoxy 281 3-pyridyl2-hydroxy-3- methoxy 422 pyrrolidin-1-yl- propoxy 282 3-chloro-phenyl2-hydroxy-3- methoxy 455 pyrrolidin-1-yl- propoxy 283 3-fluoro-phenyl3-methoxy- 3-methoxy- 442 propoxy propoxy 284 3-methoxy-phenyl3-methoxy- 3-methoxy- 454 propoxy propoxy 285 3-chloro-phenyl 3-methoxy-3-methoxy- 458 propoxy propoxy 286 3-pyridyl 3-methoxy- 3-methoxy- 425propoxy propoxy 287 3-chloro-4-fluoro- 3-methoxy-3- methoxy- 476 phenylpropoxy propoxy 288 3-chloro-4-methoxy- fluoro H 330 phenyl 2893-(1-hydroxy-ethyl)- fluoro H 310 phenyl 290 5-indolyl fluoro H 305 2913-fluoro-phenyl benzyloxy methoxy 402 297 3-(2-hydroxy-ethyl- methoxymethoxy 395 amino-carbonyl)- phenyl 298 3-[N-(3-pyrrolidin- methoxymethoxy 462 1-yl-propyl)-amino- carbonyll-phenyl 299 phenyl H fluoro 266303 3,5-di(tert-butyl)- H H 378 fluoro phenyl 309 3-chloro-4-methoxy- Hmethyl 326 phenyl 310 3-(1-hydroxy-ethyl)- H methyl 306 phenyl 3115-indolyl H methyl 301 312 3,5-di(tert-butyl)- H methyl 374 phenyl 3193-(4-methyl- methoxy methoxy 434 piperazinyl carbonyl)-phenyl 3343-fluoro-phenyl H fluoro 284 337 3-fluoro-phenyl H H 266 3385-chloro-2-methyl- H H 296 phenyl 339 2,5-difluoro-phenyl H H 284 3405-trifluoromethyl-2- H H 334 fluoro-phenyl 341 2,5-dimethoxy- H H 308phenyl 342 5-chloro-2-methoxy- H H 312 phenyl 343 3-methoxy-phenyl H H278 357 3-fluoro-phenyl fluoro methoxy 314 358 3-bromo-phenyl fluoromethoxy 375 359 3-chloro-4-fluoro- fluoro methoxy 348 phenyl 3603-methoxy-phenyl fluoro methoxy 326 361 4-fluoro-phenyl fluoro methoxy314 362 3-fluoro-phenyl hydroxy hydroxy 298 363 3-fluoro-phenyl hydroxymethoxy 312 364 3-pyridyl fluoro methoxy 297 365 3-fluoro-phenyl ethoxy3-hydroxy- 384 propoxy 366 3-methoxy-phenyl ethoxy 3-hydroxy- 396propoxy 367 3-chloro-phenyl ethoxy 3-hydroxy- 400 propoxy 3683-chloro-4-fluoro- ethoxy 3-hydroxy- 418 phenyl propoxy 3693-fluoro-phenyl bromo methoxy 375 370 3-methoxy-phenyl bromo methoxy 387371 3-pyridyl ethoxy 3-hydroxy- 367 propoxy 372 3-pyridyl 3-hydroxy-3-hydroxy- 397 propoxy propoxy 373 3-chloro-phenyl 3-hydroxy- 3-hydroxy-430 propoxy propoxy 374 3-ethoxy-phenyl methoxy methoxy 352 3753-ethoxy-phenyl ethoxy ethoxy 380 376 3-ethoxy-phenyl 3-hydroxy- methoxy396 propoxy 377 3-(2-chloro)-pyridyl methoxy methoxy 343 3793-ethoxy-phenyl 2,3-dihydroxy- methoxy 412 propoxy 382 3-fluoro-phenyl3-hydroxy- ethoxy 384 propoxy 383 3-pyridyl 3-hydroxy- ethoxy 367propoxy 384 3-methoxy-phenyl 3-hydroxy- ethoxy 396 propoxy 3883-ethoxy-phenyl ethoxy 3-hydroxy- 410 propoxy 389 3-chloro-4-fluoro-3-hydroxy- 3-hydroxy- 448 phenyl propoxy propoxy 398 3-fluoro-phenyl3-hydroxy- 3-hydroxy- 414 propoxy propoxy 400 3-methoxy-phenyl3-hydroxy- 3-hydroxy- 426 propoxy propoxy 401 3-ethoxy-phenyl 3-hydroxy-3-hydroxy- 440 propoxy propoxy 410 2-bromo-3-fluoro- methoxy methoxy 405phenyl 452 4-methyl-3-[N-[4- methoxy methoxy 492 (3-pyridyl)- pyrimidin-2-yl]amino]- phenyl 453 3-(4-methoxy)- methoxy methoxy 339 pyridyl 4543-(2,4-dimethoxy)- methoxy methoxy 369 pyridyl 460 3-fluoro-phenylethoxy 3-pyrrolidin-1- 453 yl-2-hydroxy- propoxy 461 3-pyridyl ethoxy3-pyrrolidin-1- 436 yl-2-hydroxy- propoxy 462 3-methoxy-phenyl ethoxy3-pyrrolidin-1- 465 yl-2-hydroxy- propoxy 463 3-ethoxy-phenyl ethoxy3-pyrrolidin-1- 479 yl-2-hydroxy- propoxy 476 2,6-difluoro-phenylmethoxy methoxy 344 477 2,4,6-trifluoro- methoxy methoxy 362 phenyl 5493-fluoro-phenyl methoxy benzyloxy 402 562 2-pyridyl methoxy methoxy 309565 2,2-difluoro-1,3- methoxy 388 methoxy benzodioxol-4-yl 5662,3-dihydro-1H- methoxy methoxy 334 indol-1-yl 567 5-bromo-2,3- methoxymethoxy 413 dihydro-1H-indol- 1-yl 576 2-(3-methyl-5- methoxy methoxy402 bromo)-pyridyl 577 3-(4-trifluoro- methoxy methoxy 377methyl)-pyridyl 582 2-(3-bromo)-pyridyl methoxy methoxy 388 5832-(4-bromo)-pyridyl methoxy methoxy 388 584 3-isopropoxy-phenyl methoxymethoxy 367 587 2-(3-methyl)-pyridyl methoxy methoxy 324 5882-(4,6-dimethyl)- methoxy methoxy 338 pyridyl 594 3-fluoro-phenyl ethoxyethoxy 355 608 3-fluoro-phenyl methoxy hydroxy 313

[1100] TABLE 3

Cpd G R^(B) R^(C) MS 63 benzyl methoxy methoxy 322 692-morpholin-4-yl-ethyl methoxy methoxy 345 219 3,4-dichloro-benzylmethoxy methoxy 391 220 cyclohexyl-methyl methoxy methoxy 328 2224-methyl-benzyl methoxy methoxy 336 223 2-methyl-benzyl methoxy methoxy336 224 2-methoxy-benzyl methoxy methoxy 352 225 3-methoxy-benzylmethoxy methoxy 352 230 2-chloro-benzyl methoxy methoxy 356 2314-methoxy-benzyl methoxy methoxy 352 264 benzyl ethoxy ethoxy 350 2713,5-dichloro-benzyl methoxy methoxy 390 272 3-methyl-benzyl methoxymethoxy 336 273 4-chloro-3-methyl- methoxy methoxy 370 benzyl 2742,5-dimethoxy-benzyl methoxy methoxy 382 275 3,4-difluoro-benzyl methoxymethoxy 358 293 2-fluoro-benzyl ethoxy ethoxy 368 294 3-fluoro-benzylethoxy ethoxy 368 295 2,6-dichloro-benzyl- ethoxy ethoxy 418 2962-methoxy-benzyl ethoxy ethoxy 380 301 2-trifluoromethoxy- ethoxy ethoxy434 benzyl 292 2-chloro-benzyl ethoxy ethoxy 384 304 3,5-dichloro-benzylfluoro H 349 305 3-methyl-benzyl fluoro H 294 306 3-chloro-4-methyl-fluoro H 328 benzyl 307 2,5-dimethoxy-benzyl fluoro H 340 3083,4-difluoro-benzyl fluoro H 316 313 3,5-dichloro-benzyl H methyl 345314 3-methyl-benzyl H methyl 290 315 3-chloro-4-methyl- H methyl 324benzyl 316 2,5-dimethoxy-benzyl H methyl 336 317 3,4-difluoro-benzyl Hmethyl 312 320 3,4-dimethyl-benzyl methoxy methoxy 350 3212,6-difluoro-benzyl methoxy methoxy 358 322 2,3-dimethoxy-benzyl methoxymethoxy 382 323 2,5-difluoro-benzyl methoxy methoxy 358 3241-(3-methoxy-phenyl)- methoxy methoxy 366 (S*)ethyl 325 2-fluoro-benzylmethoxy methoxy 340 326 2,3-dichloro-benzyl methoxy methoxy 391 3273-fluoro-benzyl methoxy methoxy 340 328 2,4-difluoro-benzyl methoxymethoxy 358 329 2-trifluoromethyl-benzyl methoxy methoxy 390 3302,5-dichloro-benzyl methoxy methoxy 391 331 4-fluoro-benzyl methoxymethoxy 340 333 3-chloro-benzyl methoxy methoxy 370 378 2-methyl-benzylfluoro H 296 385 2-chloro-benzyl 3-hydroxy- methoxy 400 propoxy 3862-fluoro-benzyl 3-hydroxy- methoxy 384 propoxy 387 2-fluoro-benzyl2,3-dihydroxy- methoxy 400 propoxy 390 2,6-dichloro-benzyl methoxy3-pyrrolidin-1- 504 yl-2-hydroxy- propoxy 391 2,6-difluoro-benzylmethoxy 3-pyrrolidin-1- 471 yl-2-hydroxy propoxy 396 2-chloro-benzylmethoxy 3-pyrrolidin-1- 469 yl-2-hydroxy propoxy 397 2-fluoro-benzylmethoxy 3-pyrrolidin-1- 453 yl-2-hydroxy- propoxy 424 3-chloro-benzylmethoxy methoxy 370 425 2-methyl-benzyl fluoro methoxy 324 4262-fluoro-benzyl fluoro methoxy 328 448 2,6-dichloro-benzyl 3-hydroxy-methoxy 435 propoxy 449 2,6-difluoro-benzyl 3-hydroxy- methoxy 402propoxy 450 2,6-dichloro-benzyl 2,3-dihydroxy- methoxy 451 propoxy 4512-chloro-benzyl 2,3-dihydroxy- methoxy 416 propoxy 4555-(phenyl)-isoxazol-3- methoxy methoxy 389 yl-methyl 4572,6-difluoro-benzyl 2,3-dihydroxy- methoxy 418 propoxy 5632-pyridyl-methyl methoxy methoxy 323 564 3-pyridyl-methyl methoxymethoxy 323 575 2-bromo-benzyl methoxy methoxy 401

[1101] TABLE 4

Cpd L² G A/E Ring MS 52 —(CH₂)₂— phenyl 4,5-thienyl 268 93 —(CH₂)₂—phenyl phenyl 262 94 —CH₂— phenyl 4,5-thienyl 254 95 —CH₂—3-bromo-phenyl 5,6-(1,3-benzodioxolyl) 371 96 —CH₂— 3-fluoro-phenyl5,6-(1,3-benzodioxolyl) 310 97 —CH₂— 3-methoxy- 5,6-(1,3-benzodioxolyl)322 phenyl 126 —CH₂— 3-pyridyl 5,6-(1,3-benzodioxolyl) 293 127 —CH₂—3-(methoxy- 5,6-(1,3-benzodioxolyl) 350 carbonyl)-phenyl 128 —CH₂—3-chloro-phenyl 5,6-(1,3-benzodioxolyl) 326 232 —CH₂— 3-methoxy-4,5-thienyl 284 phenyl 335 —CH₂— 3-fluoro-phenyl 4,5-thienyl 272 402—CH₂— 3-pyridyl 4,5-thienyl 255 403 —CH₂— 3-chloro-phenyl 4,5-thienyl288 404 —CH₂— 4-fluoro-3- 4,5-thienyl 306 chloro-phenyl 405 —CH₂—3-ethoxy-phenyl 4,5-thienyl 298

[1102] TABLE 5

Cpd G R^(B) R^(C) R^(1/100) MS 35 phenyl H H oxo 262 50 phenyl H Hhydroxy 264 106 4-fluoro-phenyl H H methyl 280 107 4-methoxy-phenyl H Hmethyl 292 108 3-fluoro-phenyl H H methyl 280 109 3-pyridyl H H methyl263 110 2,5-dimethoxy- H H methyl 322 phenyl 111 2,4-dimethoxy- H Hmethyl 322 phenyl 112 2,5-difluoro-phenyl H H methyl 298 1134-trifluoromethoxy- H H methyl 346 phenyl 114 4-trifluoromethyl- H Hmethyl 330 phenyl 247 phenyl methoxy methoxy methyl 322 2484-fluoro-phenyl methoxy methoxy methyl 340 249 3-fluoro-phenyl methoxymethoxy methyl 340 250 3-chloro-4-fluoro- methoxy methoxy methyl 374phenyl 251 3,5-difluoro-phenyl methoxy methoxy methyl 358 2522,5-difluoro-phenyl methoxy methoxy methyl 358 253 3-methoxy-phenylmethoxy methoxy methyl 352 254 3-benzyloxy-phenyl methoxy methoxy methyl428 255 3-methylthio-phenyl methoxy methoxy methyl 368 2563-bromo-phenyl methoxy methoxy methyl 400 257 3-chloro-phenyl methoxymethoxy methyl 356 258 2,5-dimethoxy- methoxy methoxy methyl 382 phenyl344 3-fluoro-phenyl ethoxy ethoxy methyl 368 345 3-pyridyl ethoxy ethoxymethyl 351 346 3-bromo-phenyl ethoxy ethoxy methyl 429 3474-fluoro-3-chloro- ethoxy ethoxy methyl 402 phenyl 348 3-methoxy-phenylethoxy ethoxy methyl 380 349 4-fluoro-phenyl ethoxy ethoxy methyl 368351 3-fluoro-phenyl isopropoxy isopropoxy methyl 396 352 3-pyridylisopropoxy isopropoxy methyl 379 353 3-bromo-phenyl isopropoxyisopropoxy methyl 457 354 4-fluoro-3-chloro- isopropoxy isopropoxymethyl 430 phenyl 355 3-methoxy-phenyl isopropoxy isopropoxy methyl 408356 4-fluoro-phenyl isopropoxy isopropoxy methyl 396 419 3-chloro-phenylmethoxy methoxy ethyl 370 420 3-bromo-phenyl methoxy methoxy ethyl 415421 4-fluoro-phenyl methoxy methoxy ethyl 354 482 3-bromo-phenyl methoxymethoxy (R*)ethyl 415 483 3-bromo-phenyl methoxy methoxy (S*)ethyl 415485 3-bromo-phenyl methoxy methoxy 4,4-dimethyl 415 486 3-chloro-phenylmethoxy methoxy 4,4-dimethyl 370 487 3-fluoro-phenyl methoxy methoxy4,4-dimethyl 354 488 3-methoxy-phenyl methoxy methoxy 4,4-dimethyl 366489 3-ethoxy-phenyl methoxy methoxy 4,4-dimethyl 380 504 3-ethoxy-phenylethoxy ethoxy methyl 394 505 3-ethoxy-phenyl methoxy methoxy ethyl 380512 3-methoxy-phenyl methoxy methoxy ethyl 366 538 3-bromo-phenylmethoxy methoxy 2-isopropyl 429 540 3-chloro-phenyl methoxy methoxy2-isopropyl 384 541 3-methoxy-phenyl methoxy methoxy 2-isopropyl 380 5533-bromo-phenyl methoxy methoxy (R*)methyl 401 554 3-methoxy-phenylmethoxy methoxy (R*)methyl 366 555 3-bromo-phenyl methoxy methoxy(R*)ethyl 415 556 3-methoxy-phenyl methoxy methoxy (R*)ethyl 380 5593-(2-chloro)-pyridyl methoxy methoxy (R*)methyl 357 568 3-bromo-phenylmethoxy methoxy (S*)methyl 401 569 3-ethoxy-phenyl methoxy methoxy(S*)methyl 366 570 3-bromo-phenyl methoxy methoxy (S*)ethyl 415 5713-ethoxy-phenyl methoxy methoxy (S*)ethyl 380 585 2,6-dichloro-benzylmethoxy methoxy (S*)ethyl 420 586 2,6-dichloro-benzyl methoxy methoxy(S*)methyl 405 607 3-(2-chloro)-pyridyl methoxy methoxy (R*)ethyl 371

[1103] TABLE 6

ID No A/E Ring R^(1/100) G ID-1 5,6-pyridyl H 3-fluoro-phenyl ID-25,6-pyridyl H 3-bromo-phenyl ID-3 5,6-pyridyl H benzyl ID-4 4,5-pyridylH 3-fluoro-phenyl ID-5 4,5-pyridyl H 3-methoxy-phenyl ID-6 4,5-pyridyl H3-chloro-benzyl ID-7 3,4-pyridyl H 3-fluoro-phenyl ID-8 3,4-pyridyl H3-chloro-phenyl ID-9 3,4-pyridyl H 3-fluoro-benzyl ID-10 5,6-pyrimidinylH 3-hydroxymethyl-phenyl ID-11 5,6-pyrimidinyl H 3-bromo-phenyl ID-125,6-pyrimidinyl H 2-fluoro-benzyl ID-13 4,5-pyrimidinyl H3-hydroxymethyl-phenyl ID-14 4,5-pyrimidinyl H 3-bromo-phenyl ID-154,5-pyrimidinyl H 2-fluoro-benzyl ID-16 2,3-(5-chloro-thienyl) H3-fluoro-phenyl ID-17 2,3-(5-chloro-thienyl) H 3-pyridyl ID-182,3-(5-chloro-thienyl) H 2-chloro-benzyl ID-19 4,5-(2-phenyl-furyl) Hphenyl ID-20 4,5-(2-phenyl-furyl) H 3-chloro-4-fluoro-benzyl ID-214,5-thienyl H 3-fluoro-phenyl ID-22 4,5-thienyl H 3-chloro-phenyl ID-234,5-thienyl H benzyl ID-24 3,4-furyl H 3-hydroxymethyl-phenyl ID-253,4-furyl H 3-chloro-phenyl ID-26 3,4-furyl H 2-aminosulfonyl-benzylID-27 3,4-isoxazolyl* H 3-dimethylamino-phenyl ID-28 3,4-isoxazolyl* H3-chloro-phenyl ID-29 3,4-isoxazolyl* H 2,6-dichloro-benzyl ID-304,5-(3-methyl-isoxazolyl) H 4-methoxy-phenyl ID-314,5-(3-methyl-isoxazolyl) H 3-chloro-phenyl ID-324,5-(3-methyl-isoxazolyl) H 2-fluoro-benzyl ID-33 1,2-[4,5-di(trifluoro-3-fluoro-phenyl methoxy)-phenyl] ID-34 1,2-[4,5-di(trifluoro- H3-bromo-phenyl methoxy)-phenyl] ID-35 1,2-[4,5-di(trifluoro- H3-methyl-benzyl methoxy)-phenyl] ID-36 1,2-(3,5-dimethoxy-phenyl) H3-methoxy-phenyl ID-37 1,2-(3,5-dimethoxy-phenyl) H 3-bromo-phenyl ID-381,2-(3,5-dimethoxy-phenyl) H 2-chloro-benzyl ID-391,2-(4-chloro-5-methoxy- H 3-chloro-phenyl phenyl) ID-401,2-(4-chloro-5-methoxy- H 3-bromo-phenyl phenyl) ID-411,2-(4-chloro-5-methoxy- H 3-chloro-benzyl phenyl) ID-421,2-(4-methoxy-ethoxy-5- H 3-fluoro-phenyl ethoxy-phenyl) ID-431,2-(4-methoxy-ethoxy-5- H 3-methoxy-phenyl ethoxy-phenyl) ID-441,2-(4-methoxy-ethoxy-5- H 2-methyl-benzyl ethoxy-phenyl) ID-455,6-(2-methyl-8-ethoxy- H 3-fluoro-phenyl benzoxazolyl)* ID-465,6-(2-methyl-8-ethoxy- H 3-bromo-phenyl benzoxazolyl)* ID-475,6-(2-methyl-8-ethoxy- H 2-methyl-benzyl benzoxazolyl)* ID-485,6-benzothiazolyl H 3-chloro-phenyl ID-49 5,6-benzothiazolyl H3-methoxy-phenyl ID-50 5,6-benzothiazolyl H 3-chloro-benzyl ID-511,2-(4,5-diethoxy-phenyl) H 2,3-dichloro-benzyl ID-521,2-(4,5-diethoxy-phenyl) H 3-chloro-benzyl ID-531,2-(4,5-diethoxy-phenyl) H benzyl ID-54 1,2-(4,5-di(3-methoxy- H3-fluoro-phenyl propoxy)-phenyl) ID-55 1,2-(4,5-di(methoxy- H3-methoxy-phenyl ethoxy)-phenyl) ID-56 1,2-(4,5-di(methoxy- H2-methyl-benzyl ethoxy)-phenyl) ID-57 1,2-[4,5-di(isopropoxy)- H2,3-dichloro-benzyl phenyl] ID-58 1,2-[4,5-di(isopropoxy)- H3-chloro-benzyl phenyl] ID-59 1,2-[4,5-di(isopropoxy)- H 2-methyl-benzylphenyl] ID-60 1,2-[4,5-di(isopropoxy)- methyl 2,3-dichloro-benzylphenyl] ID-61 1,2-[4,5-di(isopropoxy)- methyl 3-chloro-benzyl phenyl]ID-62 1,2-[4,5-di(isopropoxy)- methyl 2-methyl-benzyl phenyl] ID-631,2-(4,5-diethoxy-phenyl) methyl 2,3-dichloro-benzyl lD-641,2-(4,5-diethoxy-phenyl) methyl 3-chloro-benzyl ID-651,2-(4,5-diethoxy-phenyl) methyl 2-methyl-benzyl ID-661,2-(4,5-diethoxy-phenyl) H 3-(dimethylamino- ethylamino-carbonyl)-phenyl ID-67 1,2-(4,5-diethoxy-phenyl) H 3-(2-pyrrolidin-1-yl-ethylamino-carbonyl)- phenyl ID-68 1,2-(4,5-diethoxy-phenyl) H3-(2-pyrrolidin-1-yl-n- propylamino-carbonyl)- phenyl ID-691,2-(4-methoxyethoxy-5- H 3-(2-dimethylamino- ethoxy-phenyl)ethylamino-carbonyl)- phenyl ID-70 1,2-(4-methoxyethoxy-5- H3-(2-pyrrolidin-1-yl- ethoxy-phenyl) ethylamino-carbonyl)- phenyl ID-711,2-(4-methoxyethoxy-5- H 3-(3-pyrrolidin-1-yl- ethoxy-phenyl)propylamino-carbonyl)- phenyl ID-72 1,2-(4,5-diethoxy-phenyl) H3-[2-(1-methyl-imidazol- 5-yl-ethylamino- carbonyl)-phenyl] ID-731,2-(4,5-diethoxy-phenyl) H 3-[2-(imidazol-1-yl ethylamino-carbonyl)-phenyl] ID-74 1,2-(4,5-diethoxy-phenyl) H 3-[N-(3-hydroxymethyl-1-pyrrolidin-1-yl- propyl)amino- carbonyl]-phenyl ID-751,2-(4,5-diethoxy-phenyl) H 2-aminosulfonyl-phenyl ID-761,2-(4,5-diethoxy-phenyl) H 3-aminosulfonyl-phenyl ID-771,2-(4,5-diethoxy-phenyl) H 4-aminosulfonyl-phenyl ID-781,2-(4,5-di(difluoro- H 3-fluoro-phenyl methoxy)-phenyl) ID-791,2-(4,5-di(difluoro- H 3-aminosulfonyl-phenyl methoxy)-phenyl) ID-801,2-(4,5-di(difluoro- H 3-(ethoxy-carbonyl)- methoxy)-phenyl) phenylID-81 4,5-(3-ethoxy-thienyl) H 3-pyridyl-methyl ID-824,5-(3-ethoxy-thienyl) H 3-chloro-benzyl ID-83 4,5-(3-ethoxy-thienyl) Hbenzyl ID-84 4,5-(3-ethoxy-thienyl) H cyclohexylmethyl ID-854,5-(3-ethoxy-thienyl) H cyclohexylmethyl ID-86 4,5-(3-ethoxy-thienyl) Hphenethyl ID-87 5,6-pyrimidinyl H cyclohexylmethyl ID-88 5,6-pyrimidinylH phenethyl ID-89 4,5-(3-methyl-isoxazolyl) H cyclohexyl ID-904,5-(3-methyl-isoxazolyl) H 2-fluoro-phenylethyl ID-91 4,5-pyridyl H3-hydroxy-cyclohexyl ID-92 4,5-pyridyl H 2-methylbenzyl ID-934,5-pyridyl H 3-methoxy-phenyl ethyl ID-94 5,6-pyrimidinyl H4-hydroxy-cyclohexyl ID-95 5,6-pyrimidinyl H 2-hydroxymethyl-benzylID-96 5,6-pyrimidinyl H 2-fluoro-phenyl ethyl ID-97 4,5-pyrimidinyl H4-hydroxy-cyclohexyl ID-98 4,5-pyrimidinyl H 2-hydroxymethyl-befizylID-99 4,5-pyrimidinyl H 2-fluoro-phenyl ethyl ID-1001,2-(4,5-diethoxy-phenyl) H 3-pyridylmethyl ID-1011,2-(4,5-diethoxy-phenyl) H 1-methyl-5- imidazolylmethyl ID-1021,2-(4,5-diethoxy-phenyl) H 6-pyrimidinylmethyl ID-1031,2-(4,5-diethoxy-phenyl) H 3-pyridylethyl ID-1041,2-(4,5-diethoxy-phenyl) H 1-methyl-5- imidazolylmethyl ID-1051,2-(4,5-diethoxy-phenyl) H 6-pyrimidinylmethyl

[1104] TABLE 7

Cpd R^(A) R^(B) R^(C) R^(D) L² G MS 318 H H H H oxy- phenyl 278 ethylene350 H cyano H H ethylene phenyl 287 380 H H H H oxy 3-fluoro- 268 phenyl381 H H H H oxy 3-chloro-4- 302 fluoro- phenyl 595 methoxy H H H oxyphenyl 281 606 H methoxy hydroxy benzyl methylene 3-fluoro- 403 phenyl

[1105] TABLE 8

Cpd R^(A) R^(D) G MS 332 methoxy methoxy phenyl 308

[1106] TABLE 9

Cpd R^(B) R^(C) R^(1/100) R⁶ G MS 91 methoxy methoxy H methyl 3-bromo-401 phenyl 409 methoxy methoxy H 2,2-dimethyl-1-oxo- 3-fluoro- 440propoxy-methyl phenyl 427 methoxy methoxy H benzoyl 3-fluoro- 430 phenyl428 methoxy methoxy H 4-methoxy-1,4- 3-fluoro- 440 dioxo-n-butyl phenyl429 methoxy methoxy H 4-ethoxy-1,4-dioxo- 3-fluoro- 454 n-butyl phenyl430 methoxy methoxy H 1-oxo-propyl 3-fluoro- 382 phenyl 431 methoxymethoxy H 2-methyl-1-oxo- 3-fluoro- 396 propyl phenyl 432 methoxymethoxy H 2-hydroxy-1-oxo- 3-fluoro- 384 ethyl phenyl 433 methoxymethoxy H phenoxy-carbonyl 3-fluoro- 446 phenyl 438 methoxy methoxy H2-methoxy-ethoxy- 3-fluoro- 428 carbonyl phenyl 439 methoxy methoxy Hmethoxy-carbonyl 3-fluoro- 384 phenyl 446 methoxy methoxy Hdiethoxy-phosphinyl 3-fluoro- 462 phenyl 447 methoxy methoxy HN,N-dimethyl- 3-fluoro- 433 amino-sulfonyl phenyl 458 methoxy methoxy H4-methoxy-benzoyl 3-fluoro- 460 phenyl 459 methoxy methoxy H3-ethoxy-1,3-dioxo- 3-fluoro- 440 propyl phenyl 464 methoxy methoxy H5-methoxy-1,5- 3-fluoro- 454 dioxo-pentyl phenyl 465 methoxy methoxy H2-methoxy-1-oxo- 3-fluoro- 398 ethyl phenyl 466 methoxy methoxy H4-hydroxy-1,4- 3-fluoro- 426 dioxo-n-butyl phenyl 467 methoxy methoxy H2-(1-oxo-ethoxy)-1- 3-fluoro- 426 oxo-ethyl phenyl 470 methoxy methoxy H2-benzyloxy- 3-fluoro- 504 ethoxy-carbonyl phenyl 471 methoxy methoxy H2-[2-(2-hydroxy- 3-fluoro- 502 ethoxy)-ethoxyl]- phenyl ethoxy-carbonyl472 methoxy methoxy H methoxy-methyl 3-fluoro- 370 phenyl 473 methoxymethoxy H 2-(2-methoxy-1- 3-fluoro- 456 oxo-ethoxy)-1-oxo- phenyl ethyl474 methoxy methoxy H 2-(2-methoxy-1-oxo- 3-fluoro- 454 propoxy)-1-oxo-phenyl ethyl 480 methoxy methoxy H 2,6-difluoro-benzoyl 3-fluoro- 466phenyl 481 methoxy methoxy H 2-fluoro-benoyl 3-fluoro- 448 phenyl 484methoxy methoxy H 2-oxo-propyl 3-fluoro- 382 phenyl 490 methoxy methoxyH 1-oxo-butoxy- 3-fluoro- 426 methyl phenyl 492 methoxy methoxy H4-fluoro-benzoyl 3-fluoro- 448 phenyl 494 methoxy methoxy H4-chloro-benzoyl 3-fluoro- 464 methyl phenyl 496 methoxy methoxy H1-oxo-ethoxy- 3-fluoro- 398 methoxy 498 methoxy methoxy H4-(1-oxo-ethoxy)- 3-fluoro- 474 benzyl phenyl 500 methoxy methoxy H4-fluoro-phenoxy- 3-fluoro- 464 carbonyl phenyl 501 methoxy methoxy H4-chloro-phenoxy 3-fluoro- 480 carbonyl phenyl 502 methoxy methoxy H2-hydroxy-propyl 3-fluoro- 384 phenyl 506 methoxy methoxy H 5-(N-methyl-3-fluoro- 453 amino)-1,5-dioxo- phenyl pentyl 509 methoxy methoxy H2-methoxy-2-oxo- 3-fluoro- 398 ethyl phenyl 511 methoxy methoxy H2-ethoxy-2-oxo- 3-fluoro- 412 ethyl phenyl 513 methoxy methoxy H2-chloro-phenoxy- 3-fluoro- 480 carbonyl phenyl 514 methoxy methoxyethyl 2-methoxy-1-oxo- 3-bromo- 487 ethyl phenyl 516 methoxy methoxy HN-(2-amino-ethyl)- 3-fluoro- 412 amino-carbonyl phenyl 517 methoxymethoxy H N-[2-(N,N-dimethyl- 3-fluoro- 440 amino)-ethyl]- phenylamino-carbonyl 519 methoxy methoxy ethyl 2-benzyloxy-1-oxo- 3-fluoro-563 ethyl phenyl 520 methoxy methoxy H N-(2-1H-pyrrolidin- 3-fluoro- 4661-yl-ethyl)-amino- phenyl carbonyl 521 methoxy methoxy HN-(2-morpholin-4- 3-fluoro- 482 yl-ethyl)-amino- phenyl carbonyl 523methoxy methoxy H N-[2-[N-2-hydroxy- 3-fluoro- 456 yl-ethyl)-amino-phenyl amino-carbonyl 524 methoxy methoxy H N-[2-(N-methyl- 3-fluoro-426 amino-ethyl]- phenyl amino-carbonyl 525 methoxy methoxy HN-[2-[N-1-oxo- 3-fluoro- 482 1-oxo-propyl)- phenyl amino]-ethyl]-amino-carbonyl 526 methoxy methoxy H N-[2-[N-(1-oxo- 3-fluoro- 454ethyl)-amino]-ethyl]- phenyl amino-carbonyl 527 methoxy methoxy HN-[2-(2-methenyl-1- 3-fluoro- 481 oxo-propoxy)-ethyl]- phenylamino-carbonyl 530 methoxy methoxy H N-[2-(3-methyl-1- 3-fluoro- 483methoxy-1-oxo)-n- phenyl butyl]-amino- carbonyl 531 methoxy methoxy H4-amino-1,4-dioxo- 3-fluoro- 424 n-butyl phenyl 532 methoxy methoxy HN-[2-(N-benzoyl- 3-fluoro- 516 amino-ethyl]- phenyl amino-carbonyl 534methoxy methoxy H 2-amino-2-oxo-ethyl 3-fluoro- 383 phenyl 536 methoxymethoxy H 3-1H-pyrrolidin-1-yl- 3-fluoro- 465 1,3-dioxo-propyl phenyl537 methoxy methoxy H 3-(N,N-diethyl- 3-fluoro- 467 amino)-1,3-dioxo-phenyl propyl 542 methoxy methoxy H N-[2-[N-(2-hydroxy- 3-fluoro- 532benzoyl)-amino]- phenyl ethyl]-amino- carbonyl 544 methoxy methoxy HN-[2-[N-(2-hydroxy- 3-fluoro- 501 ethoxy)-ethoxy]- phenyl ethyl]-amino-carbonyl 546 methoxy methoxy ethyl benzoyl 3-bromo- 519 phenyl 547methoxy methoxy ethyl 2-[2-(2-hydroxy- 3-bromo- 591 ethoxy)-ethoxy]-phenyl ethoxy-carbonyl 548 methoxy methoxy ethyl 2-[2-(2-hydroxy-3-bromo- 577 ethoxy)-ethoxy]- phenyl ethoxy-carbonyl 572 methoxy methoxyH 2-hydroxy-ethoxy 3-fluoro- 370 phenyl 578 methoxy methoxy HN-methyl-amino- 3-fluoro- 383 carbonyl phenyl 581 methoxy methoxy HN-methyl-amino- 3-fluoro- 399 thiocarbonyl phenyl 609 methoxy methoxy Hmethyl 3-fluoro- 340 phenyl 611 methoxy methoxy H (R)3,(S)4,(S)5-3-fluoro- 503 trihydroxy-(S)6- phenyl carboxy- tetrahydro-(R)2- pyran

[1107] TABLE 10

Cpd R^(B) R^(C) R^(1/100) R⁷ G MS 300 methoxy methoxy phenyl H phenyl384 302 methoxy methoxy phenyl H 3-fluoro- 402 phenyl 395 methoxymethoxy H N-(3-fluoro- 3-fluoro- 463 phenyl)-amino- phenyl carbonyl 406methoxy methoxy H 1-oxo-ethyl 3-fluoro- 368 phenyl 407 methoxy methoxy HN-(2-ethoxy-2-oxo- 3-fluoro- 455 ethyl)-amino- phenyl carbonyl 408methoxy methoxy H 2,2-dimethyl-1- 3-fluoro- 440 oxo-propoxy- methyl 411methoxy methoxy H N-(3-ethoxy-3-oxo- phenyl 451 propyl)-amino- carbonyl412 methoxy methoxy H N-[2-(4-methyl-1- 3-fluoro- 497 methoxy-1-oxo)-phenyl pentyl]-amino- carbonyl 413 methoxy methoxy H N-[2-(3-methyl-1-3-fluoro- 483 methoxy-1-oxo)-n- butyl]-amino- carbonyl 434 methoxymethoxy H methoxy-carbonyl 3-fluoro- 384 phenyl 435 methoxy methoxy Hethoxy-carbonyl 3-fluoro- 398 phenyl 436 methoxy methoxy H1-methyl-ethoxy- 3-fluoro- 412 carbonyl phenyl 437 methoxy methoxy H2-methyl-ethoxy- 3-fluoro- 428 carbonyl phenyl 475 methoxy methoxy Hmethyl-methyl 3-fluoro- 370 phenyl 491 methoxy methoxy H 1-oxo-butoxy-3-fluoro- 426 methyl phenyl 497 methoxy methoxy H 1-oxo-ethoxy-3-fluoro- 398 methyl phenyl 499 methoxy methoxy H 4-(1-oxo-ethoxy)-3-fluoro- 474 benzyl phenyl 503 methoxy methoxy H 4-fluoro-phenoxy-3-fluoro- 464 carbonyl phenyl 510 methoxy methoxy H 2-ethoxy-2-oxo-3-fluoro- 412 ethyl phenyl 515 methoxy methoxy H 2-methoxy-1-oxo-3-bromo- 487 ethyl phenyl 518 methoxy methoxy ethyl 2-benzyloxy-1-oxo-3-fluoro- 563 carbonyl phenyl 522 methoxy methoxy H N-(2-morpholin-4-3-fluoro- 482 yl-ethyl)-amino- phenyl carbonyl 528 methoxy methoxy HN-[2-(2-methenyl- 3-fluoro- 481 1-oxo-propoxy)- phenyl ethyl]-amino-carbonyl 529 methoxy methoxy H (R)3,(S)4,(S)5- 3-fluoro- 503trihydroxy-(S)6- phenyl carboxy- tetrahydro-(R)2- pyran 535 methoxymethoxy H 3-1H-pyrrolidin-1- 3-fluoro- 465 yl-1,3-dioxo-propyl phenyl573 methoxy methoxy H 2-hydroxy-ethyl 3-fluoro- 370 phenyl 479 methoxymethoxy H N-methyl-amino- 3-fluoro- 383 carbonyl phenyl 580 methoxymethoxy H N-methyl-amino- 3-fluoro- 399 thiocarbonyl phenyl 598 methoxymethoxy H N-(pentadecyl)- 3-fluoro- 580 amino-carbonyl phenyl 602methoxy methoxy H 1-methoxy-1-oxo- 3-fluoro- 399 ethyl phenyl 604methoxy methoxy H N-[2-[2-(2-hydroxy- 3-fluoro- 502 ethoxy)-ethoxy]-phenyl ethyl]-amino- carbonyl 608 methoxy methoxy H methyl 3-fluoro- 340phenyl

[1108] TABLE 11

Cpd R^(C) R^(B) G MS 560 methoxy methyl 3-methoxy-phenyl 363 574 methoxymethyl 2-fluoro-benzyl 365 605 methoxy methyl 3-fluoro-phenyl 352

[1109] TABLE 12

Cpd R^(A) R^(B) R^(C) G MS 557 N-(1-oxo-ethyl)- methoxy methoxy3-fluoro-phenyl 383 amino 558 amino methoxy methoxy 3-fluoro-phenyl 341

[1110] TABLE 13

Cpd R^(B) R^(C) R⁴ G MS 591 methoxy methoxy (R)3,(S)4,(S)5- 3-fluoro-503 trihydroxy-(S)6- phenyl carboxy-tetrahydro- (R)2-pyran

[1111] Unless otherwise noted, the term “alkyl” as used herein, whetherused alone or as part of a substituent group, includes straight andbranched chains having 1 to 10 carbon atoms, or any number within thisrange. For example, alkyl radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl,2-methylpentyl, and the like. Unless otherwise noted, lower alkyl shallinclude straight and branched chains having 1 to 4 carbon atoms, or anynumber within this range.

[1112] Unless otherwise noted, the terms “alkoxy” or “alkyloxy” are usedsynonymously herein, and as used herein, whether used alone or as partof a substituent group, denotes an oxygen ether radical of the abovedescribed straight or branched chain alkyl groups. For example, alkoxyradicals include methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like. Specific placement of the oxygen atom inrelation to the alkyl portion is specified in the following manner,“-Oalkyl” or “-alkylO-”, to describe —OCH₃ and —CH₂O— respectively(wherein alkyl is methyl for purposes of the example).

[1113] Unless otherwise stated, “aryl,” employed alone or in combinationwith other terms (e.g., aryloxy, arylthioxy, arylalkyl), shall mean anaromatic ring structure comprising carbon atoms, for example, phenyl,naphthyl, fluorenyl, and the like.

[1114] As used herein, unless otherwise noted, “aralkyl” shall mean anylower alkyl group substituted with an aryl group such as phenyl,naphthyl and the like, for example, benzyl, phenylethyl, phenylpropyl,naphthylmethyl, and the like.

[1115] Unless otherwise noted, the term “cycloalkyl” as used herein,whether used alone or as part of a substituent group, shall mean anystable 3-10 membered, saturated ring system, for example cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[1116] Unless otherwise noted, the term “partially unsaturatedcarbocycle” as used herein, whether used alone or as part of asubstituent group, shall mean any stable 5-10 membered, partiallyunstaturated ring system, wherein the carbocycle contains, at least oneunsaturated bond, for example cyclopentenyl, cyclohexenyl,cycloheptenyl, and the like.

[1117] Unless otherwise noted, the term “heteroaryl group” as usedherein, whether used alone or as part of a substituent group, shalldenote any five to ten membered monocyclic or bicyclic aromatic ringstructure which containing carbon atoms and at least one heteroatomselected from the group consisting of O, N and S, optionally containingone to four additional heteroatoms independently selected from the groupconsisting of O, N and S. The heteroaryl group may be attached at anyheteroatom or carbon atom of the ring such that the result is a stablestructure. Examples of suitable heteroaryl groups include, but are notlimited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl,isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, and the like.

[1118] As used herein, the term “heterocycloalkyl” shall denote any fiveto ten membered monocyclic or bicyclic, saturated or partiallyunsaturated ring structure containing C atoms and at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The monocyclic or bicyclicheteroalkyl group may be attached at any heteroatom or carbon atom ofthe ring such that the result is a stable structure. Examples ofsuitable monocyclic or bicyclic heteroalkyl groups include, but are notlimited to, pyrrolinyl, pyrrolidinyl, dioxolanyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl,morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,indolinyl, chromenyl, 1,3-methylenedioxyphenyl (equivalent to benzofuseddioxolyl), 1,4-ethylenedioxyphenyl (equivalent to benzofused dioxanyl),2,3-dihydrobenzofuryl, and the like.

[1119] As used herein, unless otherwise noted, the term “benzo-fusedheteroaryl” shall mean a bicyclic ring structure wherein one of therings is phenyl and the other is a five to six membered heteroaryl. Thebenzo-fused heteroaryls are a subset of heteroaryls. Suitable exampleinclude, but are not limited to, indolyl, isoindolyl, benzofuryl,benzothienyl, indazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,cinnolinyl, phthalazinyl, quinazolinyl, pteridinyl, and the like.

[1120] As used herein, unless otherwise noted, the term “benzo-fusedheterocycloalkyl” shall mean a bicyclic ring structure wherein one ofthe rings is phenyl and the other is a five to six memberedheterocycloalkyl. The benzo-fused heterocycloalkyls are a subset of theheterocycloalkyl groups. Suitable examples include, but are not limitedto, 1,3-benzodioxolyl (also known as 1,3-methylenedioxyphenyl),indolinyl, 1,4-benzodioxolanyl (also known as 1,4-ethylenedioxyphenyl),benzodihydrofuranyl, benzotetrahydropyranyl, benzodihydrothiophene andthe like.

[1121] As used herein, unless otherwise noted, the term “benzo-fusedcycloalkyl” shall mean a bicyclic ring structure wherein one of therings is phenyl and the other is a three to eight membered cycloalkyl.Suitable examples include, but are not limited to indanyl,1,2,3,4-tetrahydronaphthyl, 6,7,8,9,-tetrahydro-5H-benzocycloheptenyl,5,6,7,8,9,10-hexahydro-benzocyclooctenyl, and the like.

[1122] As used herein, the term “linking group” is intended to refer toa divalent radical derived by, for example, the removal of at least onehydrogen atom from each of two different atoms, or the removal of twohydrogen atoms from a single atom, such that the two monovalent radicalcenters, or the single divalent radical center, form bonds withdifferent atoms.

[1123] As used herein, the term “alkyldiyl” shall include straight andbranched chain of 1 to 10 carbon atoms, or any number within this range,divalent or monovalent hydrocarbon radicals derived by the removal ofone hydrogen atom from each of two different carbon atoms, or by theremoval of two hydrogen atoms from a single carbon atom. Examplesinclude methyldiyl (also referred to herein as methylene), andethyidiyls (also referred to herein as ethylene), such asethan-1,1-diyl, and ethan-1,2-diyl.

[1124] In general, IUPAC nomenclature rules are used throughout thisdisclosure. Nomenclature for radical substituents is derived by firstindicating the functionality having the point of attachment with ahyphen, followed by the adjacent functionality toward the terminalportion of the side chain, as in:

[1125] —(C₁₋₁₀)alkyl-C(O)NH—(C₁₋₁₀)alkyl-Phenyl

[1126] or, when a lead hyphen is not used, by describing the terminalportion of the side chain first, followed by the adjacent functionalitytoward the point of attachment, as in:

[1127] phenyl-(C₁₋₁₀)alkylamido(C₁₋₁₀)alkyl, or

[1128] phenylalkylamidoalkyl

[1129] all three of which refer to a radical of the formula:

[1130] Where the are two point of attachment, for example in a linkinggroup, or a ring member, the two points of attachment are indicated witha lead hyphen and a final hypen. For example, the points of attachmentof a linking group having two monvalent radical centers would beindicated as —(CH₂)₂— or —O(CH₂)₂— and the like; and the points ofattachment of a linking group having a single divalent radical centerwould be indicated as —NH— or —N(C═O alkyl)- and the like. Points ofattachment for an aromatic ring member would be indicated as —N—., —S—or —CH— and the like, for example.

[1131] Where the phrase “terminating with” is used, the point ofattachment for the terminal substituent is indicated by the second dash.For example, for the phrase “—C(═O)—(CH₂CH₂O—)_(1,10) terminating with—H, methyl, ethyl, or benzyl” the point of attachment for the selectedterminal substituent is the terminal oxygen, for example,—C(═O)—(CH₂CH₂OH) or —C(═O)—(CH₂CH₂OCH₂CH₂OCH₂CH₂OCH₃).

[1132] When a particular group is “substituted” (e.g., phenyl, aryl,heteroalkyl, heteroaryl), that group may have one or more substituents,preferably from one to five substituents, more preferably from one tothree substituents, most preferably from one to two substituents,independently selected from the list of substituents.

[1133] With reference to substituents, the term “independently” meansthat when more than one of such substituents is possible, suchsubstituents may be the same or different from each other.

[1134] It is intended that the definition of any substituent or variableat a particular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

[1135] Compounds exemplified in the present invention were namedaccording to nomenclature well known in the art, either using AutonomVersion 2.2 (brand of nomenclature software provided in the ChemDrawUltra® 7.0.1 Office Suite marketed by CambridgeSoft.com)

[1136] Abbreviations used in the specification, particularly the Schemesand Examples, are as follows: Aq. = Aqueous ATP = Adenosine triphosphateDBU = 2,2′-Diazabicycloundecane DCM = Dichloromethane DME =Dimethoxyethylene DMF = N,N-Dimethylformamide DMSO = DimethylsulfoxideDTT = Dithiothreitol EtOAc = Ethyl acetate HPLC = High Pressure LiquidChromatography IprOH = Isopropyl alcohol MeOH = Methanol PBS = Phosphatebuffer saline PLC = Phospholipase C RAR = Rat aortic ring Sat. =Saturated SMGS = Smooth muscle growth supplement TFA = TrifluoroaceticAcid THF = Tetrahydrofuran TLC = Thin Layer Chromatography Tris HCl or =Tris[hydroxymethyl]aminomethyl hydrochloride Tris-Cl

[1137] The compounds of the present invention may be prepared by anynumber of processes as described generally below and more specificallyas described in the Examples which follow herein.

[1138] During any of the processes for preparation of the compounds ofthe present invention described herein, it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned (for example hydroxy, amino, thio, oxo or carboxygroups). This may be achieved by means of conventional protectinggroups, such as those described in Protective Groups in OrganicChemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene &P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley &Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

[1139] Methods of Synthesis

[1140] Methods of synthesizing the compounds of the present inventioninclude, but are not limited to, the methods described below. Thestarting materials used in Methods A through E are generally, startingketones of the Formula (S1)

[1141] wherein R¹, R², R³, p, q, and n are as described herein forFormula (I) Compounds of the formula (S1) are either known orcommercially available compounds or compounds which may be prepared fromknown compounds by known chemistry.

[1142] Aromatic ketones may be prepared by the Friedel-Crafts reaction(See Practical Organic Chemistry by Vogel, Third Edition, pp724-749).For example, Friedel-Crafts acylation of substituted aryl propanoicacids of formula (S1a), or their derivatives will yield substitutedindan-1-ones of formula (S1b), as described in the literature.Similarly, Friedel-Crafts acylation of substituted aryl butanoic acidsor their derivatives will yield substituted alpha-tetralones (Forexample, see Cho, H. et al., Heterocycles (1996), 43(1), 127-131;Baddeley et al., J. Chem. Soc, (1956), 4647; Reeve et al., J. Amer.Chem. Soc. (1951), 73, 1371)

[1143] Starting ketones of formula (S1b) may also be prepared from theoxidation of the corresponding alcohols of formula (S1c) or alkanes offormula (S1d) using various known oxidizing agents (For example, seeMandal, et al., Tetrahedron Lett, (1996), 37(21), 3769-3772; Ishihara,et al., J. Org. Chem. (1997), 62(17), 5664-5665).

[1144] Starting pyridyl heteroaryl ketones may be prepared bycondensation of diones of formula (S1e) or enaminones of formula (S1g)with propandiketals of formula (S1f) or propenaldehydes of formula(S1h), respectively (Examples see: Huang et al., Synth. Commun. (1998),28(7), 1197-1200; Reimann et al., Pharmazie (1995), 50(9), 589-592).

[1145] Starting thienyl heteroaryl ketones may be prepared byFriedel-Crafts acylation of heteroarylpropanoic acids using aluminumchloride, polyphosphoric acid or trifouoroacetic acid etc. to providethe cyclized ketones. (For example see Cantrell et al., Tetrahedron Lett(1967), 4477; Muraro et al., C R Hebd Seances Acad Sci (1971), 273,1362; Macdowell, et al., J. Org. Chem. (1967), 32,1226; Binder, et al.,Monatsh Chem (1998), 129(8), 887-896).

[1146] Starting furanyl heteroaryl ketones of the Formula (S1) may alsobe prepared according to procedures described Kraus et al., Synlett(1997), 11, 1259-1260; Hoye, et al., J. Org. Chem. (1990), 55 (15),4518; and Lee, et al., Bull Korean Chem. Soc. (1998),19 (10),1080-1083.

[1147] Starting pyrrolylketones may be prepared via intramolecularcyaloaddition of azomethide ylides with tethered alkynes as shown below(Nayyar, et al., J. Org. Chem. (1997), 62(4), 982-991). Alternatively,the starting pyrrole ketones may be prepared from diketones by reactingwith α-bromoketones or alpha-bromopyruvates and then by carrying outPaal-Knorr cyclization with suitably substituted amines (For example,see Stojanovic et al., J. Serb. Chem. Soc. (1997), 62(9), 749-7530. )

[1148] Thiazolyl heteroaryl ketones may be prepared via the condensationof bromoketones with thioacetamides as described in Maillard, et al.,Eur. J. Med. Chem. Ther (1984), 19 (5), 451.

[1149] Oxazole ketones and furanyl ketones may be prepared via Rhodiumcatalyzed cycloadditions of alpha-diazo-diketones with nitriles oracetylenes. Similarly, lodonium ylides may undergo Rh₂(OAc)₄ catalyzedthermal [3+2]-cycloaddition with acetylenes and nitrites to form thecorresponding furans and oxazoles, respectively. (For example see Lee,et al., Heterocycles (1998), 48(5), 875-883; and Gogonas, et. al,Tetrahedron Lett. (2000), 41(48), 9299-9303).

[1150] Starting isoxazole ketones may be prepared by cycloaddition ofN-oxides with cyclic diketones or enones in a one-step reaction as showbelow (For example see Akhrem et al., Khim. Geterotsikl. Soedin. (1974),7, 901-4; Akhrem, et al., Synthesis (1978), 1, 43).

[1151] One skilled in the art will recognize that for the preparation ofthe compounds of the instant invention, the starting materials, i.e.,compounds of Formula (S1), supra are known compounds or are compoundswhich may be prepared according to known methods, for example, asoutlined above. Starting compounds of Formula (S1) wherein n is selectedfrom 2 to 4, are similarly known compounds, or may similarly be preparedaccording to known methods or by modification of the above notedexamplary procedures.

[1152] Method A

[1153] Compounds of Formula (I) may be prepared according to the processoutlined in Method A.

[1154] Accordingly, a compound of Formula (S1), a known compound orcompound prepared by known methods, is reacted with a suitablysubstituted compound of Formula (S2), a known compound or compoundprepared by known methods, at a temperature in the range of about −78 toabout 100° C., in an aprotic organic solvent such as THF, dioxane, DMF,and the like, in the presence of a base such as lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, lithiumdiisopropylamide, and the like, to yield the corresponding compound ofFormula (S3).

[1155] The compound of Formula (S3) is reacted with hydrazine,preferably in the presence of about one equivalent of an acid such asacetic acid, hydrochloric acid, and the like, at an elevatedtemperature, preferably at about reflux temperature, to yield thecorresponding compound of Formula (I).

[1156] Examples of β-ketothioamide cyclization (S3 to I) with hydrazineforms anilinopyrrazoles similar to those described in the second step ofMethod A above, have been reported in literature (For example, see M.Suesse and S. John, J. Prakt. Chem.; (1986), 328(4), 635-9).Additionally, some ketothioamides are reported in the literatures, forexample Wesolowska et al., Pol. J. Chem. (2001), 75(3), 387-400; Hansen,et al., J. Mol. Struct. (1996), 378(1), 45-59; Augustin, et al., J.Prakt. Chem. (1979), 321(2), 205-14; Schoen et al., Rocz. Chem. (1971),45(1), 73-60.

[1157] Method B

[1158] Compounds of Formula (I) may alternatively be prepared accordingto the process outlined in Method B.

[1159] Accordingly, a compound of Formula (S1), a known compound orcompound prepared by known methods, is reacted with a compound ofFormula (S4) (1,1′-thiocarbonyldiimidazole), at a reduced temperature inthe range of about −78° C. to about 0° C., in an aprotic organic solventsuch as THF, dioxane, DMF, and the like, in the presence of a strongbase such as sodium hydride, lithium bis(trimethylsilyl) amide, sodiumbis(trimethylsilyl)amide, lithium diisopropylamide, and the like, toyield the corresponding compound of Formula (S5).

[1160] The compound of Formula (S5) is reacted with a suitablysubstituted compound of Formula (S6), a known compound or compoundprepared by known methods, in an aprotic organic solvent such as THF,dioxane, methylene chloride, chloroform, DMF, and the like, to yield thecorresponding compound of Formula (S3).

[1161] The compound of Formula (S3) is reacted with hydrazine,preferably in the presence of about one equivalent of an acid such asacetic acid, hydrochloric acid, and the like, at an elevatedtemperature, preferably at about reflux temperature, to yield thecorresponding compound of Formula (I).

[1162] The present invention is further directed to a process for thepreparation of a compound of Formula (I), as decribed in more detail inmethod B above. In one embodiment of the present invention the inventionrelates to a process for the preparation of a compound of Formula (S5),using Method B above. In another embodiment the invention relates to aprocess for the preparation of a compound of Formula (S3), using theprocess outlined in Method B above.

[1163] Method C

[1164] Compounds of Formula (I) may alternatively be prepared accordingto the process outlined in Method C.

[1165] More particularly, the compound of Formula (S1), a known compoundor compound prepared by known methods, is reacted with a suitablysubstituted compound of Formula (S2), a known compound or compoundprepared by known methods, at a temperature in the range of about 0 toabout 120° C., in an aprotic organic solvent such as THF, DMF, and thelike, in the presence of sodium hydride, to yield the correspondingcompound of Formula (S3).

[1166] The compound of Formula (S3) is reacted with hydrazine,preferably in the presence of about one equivalent of an acid such asacetic acid, hydrochloric acid, and the like, at an elevatedtemperature, preferably at about reflux temperature, to yield thecorresponding compound of Formula (I).

[1167] Method D

[1168] Compounds of Formula (I) may alternatively be prepared accordingto the process outlined in Method D.

[1169] Accordingly, a compound of Formula (S1), a known compound orcompound prepared by known methods, is reacted with carbon disulfide andmethyl iodide, in the presence of a base such as sodium hydride, lithiumbis(trimethylsilyl) amide, sodium bis(trimethylsilyl)amide, lithiumdiisopropylamide, and the like, in an aprotic organic solvent such THF,DMF, and the like, at an elevated temperature in the range of about 25°to about 100° C., to yield the corresponding compound of Formula (S7).Some compounds of Formula (S7) are known, for example as disclosed inVillemin et al., Synthesis (1991), (4), 301-3; Augustin, et al., J.Prakt. Chem. (1979), 321(2), 215-25; and in WIPO publication WO95/07893.

[1170] The compound of Formula (S7) is reacted with a suitablysubstituted compound of Formula (S6), a known compound or compoundprepared by known methods, in an aprotic organic solvent such as THF,DMF, and the like, at an elevated temperature in the range of about 25°to about 150° C., in the presence of a catalytic amount of an acid suchas acetic acid, sulfuric acid, p-toluene sulfonic acid, and the like, toyield the corresponding compound of Formula (S8).

[1171] The compound of Formula (S8) is reacted with hydrazine,preferably in the presence of about one equivalent of an acid such asacetic acid, hydrochloric acid, and the like, at an elevatedtemperature, preferably at about reflux temperature, to yield thecorresponding compound of Formula (I).

[1172] Method E

[1173] Compounds of Formula (I) may alternatively be prepared accordingto the process outlined in Method E.

[1174] Accordingly, a compound of Formula (S1), a known compound orcompound prepared by known methods, is reacted with a suitablysubstituted compound of Formula (S2), a known compound or compoundprepared by known methods, in the presence of methyl iodide and a basesuch as DBU, NaH, lithium bis(trimethylsilyl) amide, sodiumbis(trimethylsilyl)amide, lithium diisopropylamide, and the like, in anaprotic organic solvent such as acetonitrile, THF, DMF, and the like, atan elevated temperature in the range of about 0 to about 100° C., toyield the corresponding compound of Formula (S8).

[1175] The compound of Formula (S8) is reacted with hydrazine,preferably in the presence of about one equivalent of an acid such asacetic acid, hydrochloric acid, and the like, at an elevatedtemperature, preferably at about reflux temperature, to yield thecorresponding compound of Formula (I).

[1176] Method F

[1177] Compounds of Formula (II), of the structure (IIa), may beprepared according to the process outlined in Method F.

[1178] Accordingly, a compound of Formula (T1), a known compound orcompound prepared by known methods, is reacted with a suitablysubstituted compound of Formula (T2), a known compound or compoundprepared by known methods, at a temperature in the range of about −78 toabout 100° C., in an aprotic organic solvent such as THF, dioxane, DMF,and the like, in the presence of a base such as lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, lithiumdiisopropylamide, and the like, to yield the corresponding compound ofFormula (T3).

[1179] Compoud of Formula (T1) where L2 containing oxygen, sulfur ornitrogen atom can also be prepared by known methods (For example, see A.R. Deshpande, et al., Synthetic Communications, (1990), 20(6), 809-816;W -S. Li, et al., Tetrahedron Letters, (2002), 43, 1923-1925; C. Brian,et al., Tetrahedron, (1987), 43(1), 69-76; H. Winfvoid, et al., Chemie,(1970), 10(9), 343: C. Mukerjee, et al., Synletters, (2002), (2),325-327; T. Sugasawa, et al., J. Org. Chem., (1979), 44(4), 578-586:S;and Torii, et al., J. Org. Chem.,(1978), 43(14), 2882-2885.)

[1180] The compound of Formula (T3) is reacted with hydrazine,preferably in the presence of about one equivalent of an acid such asacetic acid, hydrochloric acid, and the like, at an elevatedtemperature, preferably at about reflux temperature, to yield thecorresponding compound of Formula (IIa).

[1181] Examples of β-ketothioamide cyclization (T3 to IIa) withhydrazine forms anilinopyrrazoles similar to those described in thesecond step of Method F above, have been reported in literature (Forexample, see M. Suesse and S. John, J. Prakt. Chem.; (1986), 328(4),635-9). Additionally, some ketothioamides are reported in theliteratures, for example Wesolowska et al., Pol. J. Chem. (2001), 75(3),387-400; Hansen, et al., J. Mol. Struct. (1996), 378(1), 45-59;Augustin, et al., J. Prakt. Chem. (1979), 321(2), 205-14; Schoen et al.,Rocz. Chem. (1971), 45(1), 73-60.

[1182] Method G

[1183] Compounds of Formula (II), of the structure (IIa), mayalternatively be prepared according to the process outlined in Method G.

[1184] Accordingly, a compound of Formula (T1), a known compound orcompound prepared by known methods, is reacted with a compound ofFormula (T4) (1,1′-thiocarbonyldiimidazole), at a reduced temperature inthe range of about −78° C. to about 0° C., in an aprotic organic solventsuch as THF, dioxane, DMF, and the like, in the presence of a strongbase such as sodium hydride, lithium bis(trimethylsilyl) amide, sodiumbis(trimethylsilyl)amide, lithium diisopropylamide, and the like, toyield the corresponding compound of Formula (T5).

[1185] The compound of Formula (T5) is reacted with a suitablysubstituted compound of Formula (T6), a known compound or compoundprepared by known methods, in an aprotic organic solvent such as THF,dioxane, methylene chloride, chloroform, DMF, and the like, to yield thecorresponding compound of Formula (T3).

[1186] The compound of Formula (T3) is reacted with hydrazine,preferably in the presence of about one equivalent of an acid such asacetic acid, hydrochloric acid, and the like, at an elevatedtemperature, preferably at about reflux temperature, to yield thecorresponding compound of Formula (IIa).

[1187] The present invention is further directed to a process for thepreparation of a compound of Formula (IIa), as decribed in more detailin method G above. In one embodiment of the present invention theinvention relates to a process for the preparation of a compound ofFormula (T5), using Method G above. In another embodiment the inventionrelates to a process for the preparation of a compound of Formula (T3),using the process outlined in Method G above.

[1188] Method H

[1189] Compounds of Formula (II), of the structure (IIa), mayalternatively be prepared according to the process outlined in Method H.

[1190] More particularly, the compound of Formula (T1), a known compoundor compound prepared by known methods, is reacted with a suitablysubstituted compound of Formula (T2), a known compound or compoundprepared by known methods, at a temperature in the range of about 0 toabout 120° C., in an aprotic organic solvent such as THF, DMF, and thelike, in the presence of sodium hydride, to yield the correspondingcompound of Formula (T3).

[1191] The compound of Formula (T3) is reacted with hydrazine,preferably in the presence of about one equivalent of an acid such asacetic acid, hydrochloric acid, and the like, at an elevatedtemperature, preferably at about reflux temperature, to yield thecorresponding compound of Formula (IIa).

[1192] Method I

[1193] Compounds of Formula (II), of the structure (IIa), mayalternatively be prepared according to the process outlined in Method I.

[1194] Accordingly, a compound of Formula (T1), a known compound orcompound prepared by known methods, is reacted with carbon disulfide andmethyl iodide, in the presence of a base such as sodium hydride, lithiumbis(trimethylsilyl) amide, sodium bis(trimethylsilyl)amide, lithiumdiisopropylamide, and the like, in an aprotic organic solvent such THF,DMF, and the like, at an elevated temperature in the range of about 25°to about 100° C., to yield the corresponding compound of Formula (T7).

[1195] The compound of Formula (T7) is reacted with a suitablysubstituted compound of Formula (T6), a known compound or compoundprepared by known methods, in an aprotic organic solvent such as THF,DMF, and the like, at an elevated temperature in the range of about 25°to about 150° C., in the presence of a catalytic amount of an acid suchas acetic acid, sulfuric acid, p-toluene sulfonic acid, and the like, toyield the corresponding compound of Formula (T8).

[1196] The compound of Formula (T8) is reacted with hydrazine,preferably in the presence of about one equivalent of an acid such asacetic acid, hydrochloric acid, and the like, at an elevatedtemperature, preferably at about reflux temperature, to yield thecorresponding compound of Formula (IIa).

[1197] Method J

[1198] Compounds of Formula (II), of the structure (IIa), mayalternatively be prepared according to the process outlined in Method J.

[1199] Accordingly, a compound of Formula (T1), a known compound orcompound prepared by known methods, is reacted with a suitablysubstituted compound of Formula (T2), a known compound or compoundprepared by known methods, in the presence of methyl iodide and a basesuch as DBU, NaH, lithium bis(trimethylsilyl) amide, sodiumbis(trimethylsilyl)amide, lithium diisopropylamide, and the like, in anaprotic organic solvent such as acetonitrile, THF, DMF, and the like, atan elevated temperature in the range of about 0 to about 100° C., toyield the corresponding compound of Formula (T8).

[1200] The compound of Formula (T8) is reacted with hydrazine,preferably in the presence of about one equivalent of an acid such asacetic acid, hydrochloric acid, and the like, at an elevatedtemperature, preferably at about reflux temperature, to yield thecorresponding compound of Formula (IIa).

[1201] The present invention includes compounds of Formula (II) whereinone of R⁶ or R⁷ is present and other than hydrogen (i.e., compounds offormula (IIb), (IIc), (IId), (IId), (IIe), (IIf), (IIg), (IIh), (IIj),(IIk), (IIm) (IIn), (IIo), (IIp), (IIq), (IIr) and (IIs) as defined inmore detail below). Said compounds are potentially prodrugs of compoundsof Formulae (I) and (II). The present invention further includes processfor the preparation of said compounds of formula (IIb), (IIc), (IId),(IId), (IIe), (IIf), (IIg), (IIh), (IIj), (IIk), (IIm) (IIn), (IIo),(IIp), (IIq), (IIr) and (IIs).

[1202] As prodrugs, compounds of Formula (II) wherein one of R⁶ or R⁷ ispresent and other than hydrogen are believed to be absorbed in vivo andthen metabolized or hydrolyzed to the corresponding compounds ofFormulae (I) or (II). The compounds of formula (II) wherein one of R⁶ orR⁷ is present and other than hydrogen may further have intrinsicbiological activity similar to the parent compounds of Formula (I)and/or (II).

[1203] Method L

[1204] Compounds of formula (IIb) and (IIc) wherein one of R⁶ or R⁷ isselected from the group consisting of paragraph (c) of Formula (II) maybe prepared according to the process outlined in Method L.

[1205] Accordingly, a suitably substituted compound of Formula (IIa) isreacted with a suitably substituted alkylating agent, a compound offormula (T9), a known compound, for example methyl iodide, dimethylsulfate, chloromethylpivalate, ethylene oxide, and the like, or compoundprepared by known methods, for example as halide, mesylate, tosylate,epoxide and triflate, and the like, at a temperature in a range of −70°to 100° C., in an aprotic solvent such as THF, DMF, and the like; in thepresence of a base, such as potassium carbonate, cesium carbonate,pyridine, triethylamine, diisopropylethylamine, and the like, to yield amixture of the corresponding regioisomers, compounds of formula (IIb)and (IIc). The ratio of the two regioisomers is dependent on the baseand solvent used. Preferably, the two regioisomers are separated bysilica gel column chromatography or reverse phase column chromatographyto yield compounds of formula (IIb) and (IIc).

[1206] Method M

[1207] Compounds of formula (IId) and (IIe) wherein one of R⁶ or R⁷ isselected from the group consisting of consisting of paragraphs (d), (e),(f), (g), (h) and (hh) of Formula (II) may be prepared according to theprocess outlined in Method M.

[1208] Accordingly, a suitably substituted compound of Formula (IIa) isreacted with a suitable acylating agent, a compound of formula (T11) or(T12), a known compound or compound prepared by known methods, forexample, acetyl chloride, isobutyryl chloride, succinic anhydride,methoxylacetylchloride, benzyloxylacetylchloride, benzoyl chloride, andthe like, at a temperature in a range of about between about −70° andabout 100° C., in an aprotic solvent, such as THF, DMF, pyridine and thelike, in the presence of base, such as pyridine, triethylamine,diisopropylethylamine, and the like, to yield a mixture of thecorresponding regioisomers, compounds of formula (IId) and (IIe). Theratio of the two regioisomers is dependent on the base and solvent used.Preferably, the two regioisomers are separated by silica gel columnchromatography or reverse phase column chromatography to yield compoundsof formula (IId) and (IIe).

[1209] Method N

[1210] Compounds of formula (IId) and (IIe), wherein one of R⁶ or R⁷ isselected from the group consisting of paragraphs (d), (e), (f), (g), (h)and (hh) of Formula (II) may alternatively be prepared according to theprocess outlined in Method N.

[1211] Accordingly, a suitably substituted compound of formula (IIa), isreacted with a suitably substituted carboxilc acid, a compound offormula (T13), a known compound or compound prepared by known methods,for example, 3-oxo-3-pyrrolidin-1-propionic acid, and the like, at atemperature in a range of between about −70° and about 100° C., in anaprotic solvent such as THF, DMF, and the like, in the presence of base,such as triethylamine, diisopropylethylamine, and the like, to yield amixture of the corresponding regioisomers, compounds of formula (IId)and (IIe). The ratio of the two regioisomers is dependent on the baseand solvent used. Preferably, the two regioisomers are separated bysilica gel column chromatography or reverse phase column chromatographyto yield compounds of formula (IId) and (IIe).

[1212] One skilled in the art will recognize that when the carboxylicacid of formula (T13) such as benzoic acid, propanoic acid, and thelike, the reaction is completed in the presence of a suitable peptidecoupling reagent, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(EDC) and hydroxybenzotriazole hydrate (HOBT), and the like.

[1213] Method O

[1214] Compounds of formula (IIf) and (IIg), wherein one of R⁶ or R⁷ isselected from the group consisting of paragraphs (i), (j), and (k) ofFormula (II) may may be prepared according to the process outlined inMethod O.

[1215] Accordingly, a suitably substituted compound of formula (IIa) isreacted with a suitably substituted chloroformate, a compound of formula(T14), a known compound or compound prepared by known methods, forexample, ethyl chloroformate, 2-methoxyethyl chloroformate,isopropylchloroformate, tri(ethyleneglycol), bis(chloroformate), and thelike, at the temperature in a range of between about −70° and bout 100°C., in an aprotic solvent such as THF, DMF, DCM, and the like, in thepresence of base such as pyridine, triethylamine, diisopropylethylamine,and the like, to yield a mixture of the corresponding regioisomers,compounds of formula (IIf) and (IIg). The ratio of the two regioisomersis dependent on the base and solvent used. Preferably, the tworegioisomers are separated by silica gel column chromatography orreverse phase column chromatography to yield compounds of formula (IIf)and (IIg).

[1216] Method P

[1217] Compounds of formula (IIh) and (IIj), wherein one of R⁶ or R⁷ isselected from the group consisting of paragraphs (I), (m), (n) and (o)of Formula (II) may be prepared according to the process outlined inMethod P.

[1218] Accordingly, a suitably substituted compound of Formula (IIa) isreacted with a suitably substituted aryl chloroformate, a compound offormula (T15), a known compound or compound prepared by known methods,for example, phenyl chloroformate, 4-nitrophenyl chloroformate, and thelike, at a temperature in a range of between about −70° and about 100°C., in an aprotic solvent, such as THF, DMF, DCM, and the like, in thepresence of base such as pyridine, triethylamine, diisopropylethylamine,and the like, to yield a mixture of the corresponding regioisomers,compounds of formula (T16) and (T17). Compounds of formula (T16) and(T17) are separated by silica gel column chromatography or reversecolumn chromatography.

[1219] The compounds of formula (T16) and (T17), separately, are reactedwith a suitably substituted amine, a compound of formula (T18), a knowncompound or compound prepared by known methods, for example,1-methyl-1-ethyl-1,2-diamine, propylamine,3-(morpholin-4-yl)-1-propylamine, and the like, in an aprotic solventsuch as DMF, DMSO, THF, and the like, at the temperature in a range ofbetween about −70° and about 100° C. to yield the correspondingcompounds of formula (IIh) and (IIj).

[1220] Alternatively, the compounds of formula (T16) and (T17) as amixture are reacted with a suitably substituted amine, a compound offormula (T18), to yield a mixture of compounds of formula (IIh) and(IIj). The compounds of formula (IIh) and (IIj) are then separated byknown methods, for example by silica gel column chromatography orreverse phase column.

[1221] Both sequences give the desired compounds of formula (IIh) and(IIi). Preparation of a library of compounds is achieved moreefficiently by reacting the compounds of formula (T16) and (T17)separately than by reacting a mixture of compounds of formula (T16) and(T17) followed by separation.

[1222] Method Q

[1223] Compounds of formula (IIk) and (IIm), wherein one of R⁶ or R⁷ isselected from the group consisting of paragraphs (l), (m), (n), (o), (p)and (q) of Formula (II) may be prepared according to the processoutlined in Method Q.

[1224] Accordingly, a suitably substituted compound of Formula (IIa) isreacted with a suitably substituted isocyanate, a compound of formula(T19) or a suitably substituted thioisocyanate, a compound of formula(T20), for example, phenylisocyanate, methylisocyanate,methylthioisocyanate, and the like, at a temperature in a range ofbetween about −20° and about 100° C., in an aprotic solvent, such asTHF, DMF, DCM, and the like, in the presence of base, such as pyridine,triethylamine, diisopropylethylamine, and the like, to yield a mixtureof the corresponding regioisomers, compounds of formula (IIk) and (IIm).The ratio of the two regioisomers is dependent on the base and solventused. Preferably, the two regioisomers are separated by silica gelcolumn chromatography or reverse phase column chromatography to yieldcompounds of formula (IIk) and (IIm).

[1225] One skilled in the art will recognize that when the compound offormula (IIa) is reacted with an isocyanate, then the correspondingcompounds of formula (IIk) and (IIm) will have R⁶ or R⁷ substituents of—C(O)NHR′″″. Similarly, when the compound of formula (IIa) is reactedwith an thioisocyanate, then the corresponding compounds of formula(IIk) and (IIm) will have R⁶/or R⁷ substituent of —C(S)NHR′″″.

[1226] Method R

[1227] Compounds of formula (IIn) and (IIo), wherein one of R⁶ or R⁷ isselected from the group consisting of paragraphs (s), (t) and (u) ofFormula (II) may be prepared according to the process outlined in MethodR.

[1228] Accordingly, a suitably substituted compound of Formula (IIa) isreacted with a suitably substituted sulfamoyl chloride, a compound offormula (T21), a known compound, for example, dimethylsulfamoylchloride, ethylsulfamoyl chloride, and the like, or a compound preparedby known methods, at a temperature in a range of between about −20° andabout 100° C., in an aprotic solvent, such as THF, DMF, DCM, and thelike, in the presence of base, such as pyridine, triethylamine,diisopropylethylamine, and the like, to yield a mixture of thecorresponding regioisomers, compounds of formula (IIn) and (IIo). Theratio of the two regioisomers is dependent on the base and solvent used.Preferably, the two regioisomers are separated by silica gel columnchromatography or reverse phase column chromatography to yield compoundsof formula (IIn) and (IIo).

[1229] One skilled in the art will recognize that when the compound offormula (IIa) is reacted with an sulfamyl, then the correspondingcompounds of formula (IIo) and (IIp) will have R⁶ or R⁷ substituents of—SO₂NHR″″″ and —SO₂N(R″″″)₂.

[1230] Method S

[1231] Compounds of formula (IIp) and (IIq), wherein one of R⁶ or R⁷ isselected from the group consisting of paragraphs (v) and (w) of Formula(II) may be prepared according to the process outlined in Method S.

[1232] Accordingly, a suitably substituted compound of Formula (IIa) isreacted with a suitably alkyl chlorophosphate, a compound of formula(T22), a known compound, for example, dimethylchlorophosphate,diethylchlorophosphate, and the like, or a compound prepared by knownmethods, at a temperature in a range of between about −20° and about100° C., in an aprotic solvent, such as THF, DMF, DCM, and the like, inthe presence of base, such as pyridine, triethylamine,diisopropylethylamine, and the like, to yield a mixture of thecorresponding regioisomers, compounds of formula (IIp) and (IIq). Theratio of the two regioisomers is dependent on the base and solvent used.Preferably, the two regioisomers are separated by silica gel columnchromatography or reverse phase column chromatography to yield compoundsof formula (IIp) and (IIq).

[1233] One skilled in the art will recognize that when the compound offormula (IIa) is reacted with a dialkyl chlorophosphate, then thecorresponding compounds of formula (IIp) and (IIq) will have R⁶ or R⁷substituents of —P(═O)(O(C₁-C₃)alkyl)₂

[1234] Method T

[1235] Compounds of formula (IIr) and (IIs), wherein one of R⁶ or R⁷ isselected from the group consisting of paragraph (r) of Formula (II) maybe prepared according to the process outlined in Method T.

[1236] Accordingly, a suitably substituted compound of Formula (IIa) isreacted with a suitably substituted aryl thionochloroformate, a compoundof formula (T23), a known compound or compound prepared by knownmethods, for example, phenylthionochloroformate, and the like, at atemperature in a range of between about −70° and about 100° C., in anaprotic solvent, such as THF, DMF, DCM, and the like, in the presence ofbase such as pyridine, triethylamine, diisopropylethylamine, and thelike, to yield a mixture of the corresponding regioisomers, compounds offormula (T24) and (T25). Compounds of formula (T24) and (T25) areseprated by silica gel column chromatography or reverse phase columnchromatography.

[1237] The compounds of formula (T24) and (T25), separately are reactedwith a suitably substituted amine, a compound of formula (T26), a knowncompound or compound prepared by known methods, for example, piperidine,morpholine. Dimethylamine, pyrrolidine and the like, in an aproticsolvent such as DMF, DMSO, THF, and the like, at the temperature in arange of between about −70° and about 100° C. to yield the correspondingcompounds of formula (IIr) and (IIs).

[1238] Alternatively, the compounds of formula (T24) and (T25) as amixture are reacted with a suitably substituted amine, a compound offormula (T26), to yield a mixture of compounds of formula (IIr) and(IIs). The compounds of formula (IIr) and (IIs) are then separated byknown methods, for example by silica gel column chromatography orreverse phase column.

[1239] Both sequences give the desired compounds of formula (IIr) and(IIs). Preparation of a library of compounds is achieved moreefficiently by reacting the compounds of formula (T24) and (T25)separately than by reacting a mixture of compounds of formula (T24) and(T25) followed by separation.

[1240] N-Glucuronide Synthesis

[1241] To varying degrees the compounds of this invention may undergothe in vivo N-glucuronidation by various endogenous isozymes of theUDP-glucuronosyltransferase family (Chiu, S -H L; Huskey, S -E W; 1996ASPET N-glucuronidation of xenobiotics symposium: Species differences inN-glucuronidation, Drug Metabolism and Disposition 1998, 26(9):838-847).

[1242] One skilled in the art will understand that in vivo metabolitesof compounds of Formulae (I) and (II) may be readily reverted tocompounds of Formulae (1) and (II) by action of endogenousβ-glucuronidase. The scientific literature details that tumor tissuegenerally contains elevated levels of endogenous β-glucuronidase. Byaction of endogenous β-glucuronidase, the in situ re-generation ofcompounds of Formulae (I) and (II) can be accomplished. In this way, theability of the compounds of the present invention to be reversiblyglucuronidated allows for the targeting of the present compounds totumor tissue (Sperker, B; Backman, J T; Kroemer, H K, The role ofβ-glucuronidase in drug disposition and drug targeting in humans, Clin.Pharmacokinet., 1997, 33(1): 18-31).

[1243] Furthermore, reversible glucuronidation of the present compoundsmay also be recognized by one skilled in the art as a potential methodfor the detoxification of compounds of Formulae (I) and (II) (Caldwell,J; The significance of phase II conjugation reactions in drugdisposition and toxicity, Life Sci, 1979, 24: 571-578), thus allowingthe N-glucuronide metabolites formed to serve as a potential non-toxicreservoir for compounds of Formulae (I) and (II) which can then bereadily unmasked to fully biologically active compounds of Formulae (I)and (II) in situ by tumor associated β-glucuronidase.

[1244] The N-glucuronide metabolites of compounds of Formulae (I) and(II) will have the structures shown below as GLU A, GLU B, and GLU C:

[1245] Usually, the glucuronidated compounds will have a β-configurationabout the anomeric carbon atom, especially if the glucuronide isproduced by well-established enzymatic methods known to persons skilledin the art (Luukkanen, L; Kilpelaeinen, I; Kangas, H; Ottoila, P;Elovaara, E; Taskinen, J, Enzyme-Assisted Synthesis and StructuralCharacterization of Nitrocatechol Glucuronides, Bioconjugate Chemistry(1999), 10(1), 150-154).

[1246] The N-glucuronides may also be prepared by direct synthesis byreacting compounds of Formulae (I) and (II) with suitably protectedglucuronosyl halides by synthetic methodology know to persons skilled inthe art (Upadhyaya, Pramod; Mclntee, Edward J.; Hecht, Stephen S.,Preparation of Pyridine-N-glucuronides of Tobacco-SpecificNitrosamines., Chemical Research in Toxicology (2001), 14(5), 555-561).

[1247] One skilled in the art will recognize that the GLU A, GLU B andGLU C derivatives of the compounds of Formulae (I) and (II) may beprepared by known methods, by adapting the procedures cited above.

[1248] Alternative Methods

[1249] One skilled in the art will further recognize that the R² and/orR³ groups on the

[1250] and/or

[1251] rings may alternatively be incorporated into the compound ofFormula (I) by known methods, after formation of the core structure ofFormula (I), a compound of Formula (Icore)

[1252] wherein each Z is bound directly to the

[1253] ring or to a portion of an R² or R³ substituent (for examplewherein the desired R² group is X-A¹-Y-A², the Z group may be bound toan X-A¹ group bound to an

[1254] For example, if one or more of the Z groups are hydroxy, thehydroxy group may be reacted according to known methods with an alkylhalide, to form the corresponding —O-alkyl substituent; withCl—C(O)-alkyl or Cl—C(O)-aryl to form the corresponding —C(O)-alkyl or—C(O)-aryl substituent; with Cl—C(O)O— alkyl or Cl—C(O)O-aryl to formthe corresponding —C(O)O-alkyl or —C(O)O-aryl substituent; or withC(O)N(alkyl) or C(O)C(aryl) to form the corresponding —OC(O)N(alkyl) or—OC(O)N(aryl) substituent.

[1255] If one or more of the Z groups is amino, the amino group may bereacted according to known methods with HC(O)-alkyl or HC(O)-aryl toform the corresponding —NHCH₂-alkyl or —NHCH₂-aryl substituent; withCl—C(O)-alkyl or Cl—C(O)-aryl to form the corresponding —NHC(O)-alkyl or—NHC(O)aryl substituent; with C(O)N-alkyl or C(O)N-aryl to form thecorresponding —NHC(O)NH-alkyl or —NHC(O)NH-aryl substituent; withCl—C(O)O-alkyl or Cl—C(O)O-aryl to form the corresponding —NHC(O)O-alkylor —NHC(O)O-aryl substituent; or with Cl—SO₂-alkyl or Cl—SO₂-aryl toform the corresponding —NHSO₂-alkyl or —NHSO₂-aryl substituent. Oneskilled in the art will further recognize that if the Z group is analkyl amino or aryl amino group, similar chemistry may be preformed toyield corresponding substituents where the N group bound directly to theA or B ring remains substituted with the alkyl or aryl group.

[1256] If one or more of the Z groups is thio, the thio group may bereacted according to known methods with an alkyl halide to form thecorresponding alkyl thio substituent. If one or more of the Z groups isalkylthio, the alkylthio group may be reacted according to known methodsto form the corresponding alkyl sulfonyl substituent.

[1257] If one or more of the Z groups is carboxy, the carboxy group maybe reacted according to known methods to form the corresponding —C(O)Clgroup, which in turn may be further reacted to form the desired R²and/or R³ substituents.

[1258] If one or more of the Z groups is —C(O)Cl, the —C(O)Cl group maybe reacted according to known methods with an alkoxy to form thecorresponding —C(O)O-alkyl substituent; with —NH(alkyl) or N(alkyl)₂ toform the corresponding —C(O)NH(alkyl) or —C(O)N(alkyl)₂ substituent.

[1259] If one or more of the Z groups is a halogen such as iodine orbromine, the halogen may be reacted according to known methods withB(OH)₂-alkyl, B(OH)₂-aryl or B(OH)₂-heteroaryl to displace the halogenwith the corresponding -alkyl, -aryl or -heteroaryl group.

[1260] Alternatively, if one or more of the Z groups is a halogen suchas iodine or bromine, the halogen may be reacted according to knownmethods with an alkylamine, a dialkylamine, an arylamine, aheteroarylamine or a heterocycloalkylamine to displace the halogen withthe corresponding —NH— alkyl, —N(alkyl)₂, —N-aryl, —NH-heteroaryl or—NH-heterocycloalkyl group.

[1261] Alternatively, if one or more of the Z groups is a halogen suchas iodine or bromine, the halogen may be reacted according to knownmethods with HO-alkyl, HO-aryl, HO-heteroaryl or HO-heterocycloalkyl todisplace the halogen with the corresponding —O-alkyl, —O-aryl,—O-heteroaryl or —O-heterocycloalkyl group.

[1262] Alternatively, if one or more of the Z groups is a halogen suchas iodine or bromine, the halogen may be reacted according to knownmethods with HS-alkyl, HS-aryl, HS-heteroaryl or HS-heterocycloalkyl todisplace the halogen with the corresponding —S-alkyl, —S-aryl,—S-heteroaryl or —S-heterocycloalkyl group.

[1263] If one or more of the Z groups is —O—SO₂-aryl or —OSO₂-alkyl, the—O—SO₂aryl or —OSO₂-alkylgroup may be reacted according to known methodswith an alkyl amine, a dialkylamine an aryl amine or a heteroarylaminoto form the corresponding —NH(alkyl), —N(alkyl)₂, —NH(aryl) or—NH(heteroaryl) group.

[1264] Alternatively, If one or more of the Z groups is —O—SO₂-aryl or—OSO₂-alkyl, the —O—SO₂aryl or —OSO₂-alkylgroup may be reacted accordingto known methods to displace the —O—SO₂ group with a halogen such as Bror I, to form a reactive intermediate which can then be further reactedto form the desired substituent.

[1265] If one or more of the Z groups is —S-alkyl, —S-aryl,—S-heteroaryl or —S-heterocycloalkyl, the S may be oxidized according toknown methods to form the corresponding —SO₂-alkyl, —SO₂-aryl, —SO₂-heteroaryl or —SO₂-heterocycloalkyl substituent.

[1266] If one or more of the Z groups contains a terminal unsaturatedbond, the Z group may be reacted according to known methods to form thecorresponding epoxide, which in turn may be reacted with a substitutedamine such as an alkylamino, a dialkylamine, an arylamine, aheteroarylamine, a heterocycloalkylamine, or a cyclic amine (such aspiperidine, morpholine, imidazole, and the like), to form thecorresponding —CH(OH)CH₂—NH-alkyl, —CH(OH)CH₂—N(alkyl)₂,—CH(OH)CH₂—NH-aryl, —CH(OH)CH₂—NH-heteroaryl,—CH(OH)CH₂—NH-heterocycloalkyl or —CH(OH)CH₂-(cyclic amine bound throughthe N atom) substituent.

[1267] One skilled in the art will further recognize transformation orreactions similar to those described above may be employed in (orapplied to) the preparation of compounds of formula (II). Moreparticularly, the processes described above for the introduction of R²and/or R³ groups on the

[1268] and/or

[1269] rings may be used to incorporate R⁵, R⁹ and/or R¹⁰ substituentsonto the

[1270] and rings on the compounds of formula (II).

[1271] One skilled in the art will recognize that compounds of Formula(I) wherein R¹ is oxo (═O) may be converted according to known methodsto form compounds of Formula (I) wherein R¹ is hydroxy (by reduction) orconverted to intermediate compounds wherein R¹ is ═NHOH (by reactingwith NH₄OH). The intermediate compounds wherein R¹ is ═NHOH may then bereduced according to known methods to the corresponding amine, which maythen be further optionally functionalized to the correspondingsubstituted amine.

[1272] Compounds of Formula (I) wherein R¹ is hydroxy may be convertedaccording to known methods to form intermediate compounds wherein R¹ is—O—SO₂-aryl or —O—SO₂-alkyl by reacting the intermediate compound withthe corresponding Cl—SO₂-aryl or Cl—SO₂-alkyl reagent. The —O—SO₂-arylor —O—SO₂-alkyl R¹ group may then be further optionally reactedaccording to known methods to form an amine (by reacting with NaN₃followed by reduction).

[1273] Alternatively, compounds of Formula (I) wherein R¹ is hydroxy maybe converted according to known methods to form compounds of Formula (I)wherein R¹ is —O-alkyl by reacting with the corresponding alkyl halide.

[1274] Compounds of Formula (I) wherein R¹ is amine or alkyl amine maybe reacted according to known methods to form compounds of Formula (I)wherein R¹ is —NH—CH₂-alkyl or —NH—(CH₂-alkyl)₂ by reacting withHC(O)-alkyl.

[1275] One skilled in the art will further recognize that transformationor reactions similar to those described above may be employed in (orapplied to) the preparation of compounds of formula (II). Moreparticularly, the processes described above for the introduction andoptional conversion of R¹ groups in the compounds of formula (I) may besimilarly applied to the preparation of compounds of formula (II),wherein such transformations are appropriate in the preparation ofdesired L² groups.

[1276] One skilled in the art will further recognize that the aboveexamples for the inclusion of desired substituent groups into thecompounds of Formula (I) and/or compounds of formula (II) are notintended to be all inclusive, but rather are intended to provideexamples of known chemistry for the incorporation of representativesubstituents. Additional substituents groups not specifically describedherein may be incorporated into the compounds of Formula (I) and/orcompounds of formula (II) by known methods.

[1277] Representative compounds of the present invention synthesized bythe aforementioned methods are presented below. Examples of thesynthesis of specific compounds are presented thereafter. Cpd Structure1

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[1278] The following examples are given for the purpose of illustratingvarious synthetic methods for compounds of the invention and are notmeant to limit the present invention in any fashion.

EXAMPLE 1

[1279] 1-Oxo-indan-2-carbothioic acid phenylamide, Intermediate A(Method A)

[1280] NaH (60% dispersion in mineral oil, 0.25 g, 6 mmol) andindan-1-one, Compound 1a, (0.50 g, 3.79 mmole) in THF (5 mL) were mixedunder argon. The mixture was stirred at ambient temperature for 5 min.Then, phenylisothiocyanate, Compound 1b, (0.46 mL, 3.79 mmole) was addedto the mixture. After an additional 5 min, the reaction was completed asshown by TLC analysis and the reaction mixture was poured into NH₄Clsolution and then filtered subsequently. 1-Oxo-indan-2-carbothioic acidphenylamide (Intermediate A), was crystallized from CH₃CN as a yellowsolid. MS m/z 268 (M+H)⁺; ¹H NMR (DMSO-d₆): 3.5 (dd, 0.3H), 3.8 (d,0.15H), 3.9 (s, 1.55H), 4.3 (dd, 0.3H), 7.3 (t, 1H), 7.4-7.8 (m, 7.4H),7.9 (d, 0.6H), 10.6 (s, 0.7H), 12.1 (s, 0.3H), 14.1 (s, 0.7H).

EXAMPLE 2

[1281] 2,4-Dihydro-indeno[1,2-c]pyrazol-3-yl)-phenyl-amine, Compound 1(Method A)

[1282] (Intermediate A) 1-Oxo-indan-2-carbothioic acid phenylamide (0.35g, 1.31 mmole), ethanol (2 mL) and hydrazine (0.043 mL 1.38 mmole) weremixed in a flask under argon. The reaction mixture was heated on a steambath for 1 hour, then cooled and the solvent evaporated to a brown oil.The oil was further dissolved in CH₂Cl₂, and was washed with 1N HCl, 3NNaOH and brine. The resulting organics (0.31 g) were dried (Na₂SO₄),filtered, and the solvent was removed in vacuo. The product was isolatedby silica gel chromatography with 2% methanol:methylene chloride. Thetitle compound (Compound 1) was subsequently crystallized frommethylcyclohexane:toluene as a white solid. m.p. 148-149° C.; MS m/z 248(M+H)⁺; ¹H NMR (DMSO-d₆): 3.5 (s, 2H), 6.75 (t, 1H), 7.0-7.3 (m, 5H),7.35 (t,1H), 7.5 (dd, 2H), 8.4 (s, 1H), 12.3 (s, 1H).

EXAMPLE 3

[1283](3,5-Dichloro-phenyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine,Compound 19 (Method A)

[1284] A mixture of 5,6-dimethoxyindan-1-one, Compound 3a, (4 g, 0.021mole), 3,5-dichlorophenyl isothiocyanate, Compound 3b, (4.45 g, 0.022mole) and THF (30 mL) was added to lithium hexamethyldisilane (26.9 mL,0.269 mole) dropwise at room temperature with stirring. Hydrazine (1.04mL, 0.032 mole) and acetic acid (1.65 mL) were added to the reactionmixture, which was then stirred at room temperature for 12 hrs. Thereaction continued at 75° C. overnight. The resulting organics werefirst diluted with ethyl acetate (100 mL), then washed with water andbrine solution, dried (Na₂SO₄), and solvent was removed in vacuo. Thechemical residues were recrystallized from ethanol. The first and secondcrops of solid were combined and dissolved in hot CH₃CN, to which anequal volume of HCl-ether solution was added to precipitate the titlecompound (Compound 19), which was collected and dried under vacuum at60° C. mp>270° C.; MS m/z 376 and 378 (M+H)⁺; ¹HNMR (DMSO-d₆):3.44(s,2H), 3.83(s,3H), 3.82(s,3H),6.93(s,1H),7.19 (s,1H), 7.21(s,1H),7.35(s,2H).

EXAMPLE 4

[1285](3-Fluoro-phenyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine,Compound 14 (Method A)

[1286] A mixture of 5,6 dimethoxyindan-1-one, Compound 3a, (3.0 g,0.0154 mole), 3-fluoro-phenyl isothiocyanate, Compound 4a, (2.4 g,0.0157 mole) and THF (3.0 mL) was added to lithium hexamethyldisilane(15.4 mL, 0.0154 mole) dropwise at room temperature with stirring. Thereaction mixture was stirred for 12 hrs. Hydrazine (0.75 mL, 0.0154mole) and acetic acid (0.96 mL) were added to the reaction mixture,which was then heated at the reflux temperature for 24hrs. The resultingmixture was first added to water (30 mL) and then extracted with CH₂Cl₂.The organic layers were combined and washed with aqueous NaHCO₃solution, then washed with water and brine solution, dried (Na₂SO₄), andsolvent was removed in vacuo. The residue was dissolved in hot CH₃CN. Tothe mixture was then added one equivalent of an HCl-ether solution toyield a precipitate of the title compound. The precipitate was dissolvedin CH₃CN and decolorized with charcoal and re-crystallized to giveCompound 14 as an off white solid. MS m/z 326 (M+H)⁺; ¹HNMR (DMSO-d₆):3.44(s, 2H), 3.80(s, 3H), 3.81(s, 3H), 6.58(t, 1H), 6.85 (d, 1H), 7.1(d,1H), 7.21(s, 1H), 7.23(s, 1H), 7.3(m, 1H), 9.2(br s, 1H).

EXAMPLE 5

[1287] 2-(Imidazole-1-carbothioyl)-5,6-dimethoxy-indan-1-one,Intermediate B (Method B)

[1288] Lithium bis(trimethylsilyl)amide in THF (11 mL, 11 mmol) and THF(20 mL) were mixed with stirring in a dry flask under a nitrogenatmosphere. 5,6 dimethoxyindan-1-one (1.92 g, 10 mmol) in 15 mL THF wasadded to the flask. The reaction mixture was then cooled in adry-ice-acetone bath. The reaction solution was stirred at −78° C. andthiodiimidazole (2.18 g, 11 mmol) in 15 mL of THF was added. Thereaction mixture was stirred at −78° C. for 5 hrs, then quenched with 40mL of saturated NH₄Cl solution, and warmed to room temperature. Theaqueous solution of the mixture was extracted with ethyl acetate twiceto yield the title compound in the organic solution. The mixture waswashed with water and saturated NaCl solution, dried (Na₂SO₄), andsolvent was removed in vacuo.2-(Imidazole-1-carbothioyl)-5,6-dimethoxy-indan-1-one was obtained as ayellow solid. HPLC analysis showed the product was pure. MS m/z 303(M+H)⁺; ¹HNMR (DMSO-d₆): 3.60(s, 2H), 3.70(s, 3H), 3.85(s,3H),6.90(s,1H), 7.1(s, 1H), 7.51(s,1H), 7.60(s,1H), 9.1(s,1H).

EXAMPLE 6

[1289][3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-phenyl]-methanol,Compound 36 (Method B)

[1290] 2-(Imidazole-1-carbothioyl)-5,6-dimethoxy-indan-1-one,Intermediate B, (1.0 g, 3.3 mmol) was mixed with 3-aminobenzyl alcohol(0.40 g, 3.3 mmol), and 30 mL THF in a flask.5,6-Dimethoxy-1-oxo-indan-2-carbothioic acid(3-hydroxymethyl-phenyl)-amide was obtained after stirring the reactionmixture for 4 hours at room temperature. HPLC/MS m/z 358 (M+H)⁺. Theintermediate was not isolated, the mixture was mixed with hydrazine(0.13 mL, 4 mmol), and acetic acid (2-3 drops). The reaction was heatedat 78° C. for 12 hours. The reaction solution was then diluted withethyl acetate, washed with water, and dried over Na₂SO₄. The solvent wasremoved and the title compound was purified by HPLC with a C-18 reversedphase column and CH₃CN—H₂O-TFA as gradient solvents. The title compound,[3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-phenyl]-methanol,Compound 36, was obtained as a solid TFA salt. MS m/z 338 (M+H)⁺;HPLC:100% (uv 214 mu);

[1291]¹HNMR (DMSO-d₆): 3.40(s, 2H), 4.54(s, 2H), 6.81 (d, 1H), 7.02 (d,1H), 7.14(s, 1H), 7.22(d, 2H).

EXAMPLE 7

[1292] N3-Phenyl-2,4-dihydro-indeno[1,2-c]pyrazole-3,6-diamine, Compound66 (Method C)

[1293] NaH (60% dispersion in mineral oil (0.25 g, 6 mmol)) and dry THF(25 mL) were mixed in a flask under an Argon atmosphere.5-aminoindan-1-one, Compound 7a, (0.22 g, 15 mmol) andphenylisothiocyanate, Compound 1b, (0.18 mL, 15 mmol) were then added tothe reaction with stirring. After the reaction mixture was stirred atroom temperature for one hour, hydrazine (0.45 mL, 75 mmol) followed byacetic acid (0.070 mL, 2.25 mmol) was added. The reaction was continuedat 70° C. with stirring overnight. The reation was diluted withsaturated aq. NaHCO₃, extracted with ethyl acetate, washed with brine,dried over sodium sulfate and the solvent was removed in vacuo. Thecrude material was purified by HPLC to yield the title compound(Compound 66) as a TFA salt. MS m/z 263 (M+H)⁺; ¹HNMR (DMSO-d₆):3.50(s,2H), 6.80(m,1H), 6.98(m,1H), 7.14(m,3H), 7.24(m,2H), 7.32(t,1H),7.49(d,1H), 7.56(d,1H), 8.80(bs,1H);

[1294] HPLC: 100% (uv 214).

EXAMPLE 8

[1295] 2-(Bis-methylsulfanyl-methylene)-5,6-dimethoxy-indan-1-one,Intermediate D (Method D)

[1296] NaH (60% dispersion in mineral oil; 3.37 g, 44.3 mmol), carbondisulfide (3.37 g, 44.3 mmol) and THF (50 mL) were added to a dry flaskunder Nitrogen. The reaction flask was cooled with an ice-water bath andthen 5,6-dimethoxy-indan-1-one, Compound 3a, (7.1 g, 37 mmol) in THF (50mL) was added. The reaction mixture was stirred for 1 h. Then,methyliodide (5.2 mL, 44.3 mmol) was added. The resulting reactionsolution was allowed to stir at room temperature overnight, then anaqueous NH₄Cl solution (150 mL) was added followed by ethyl acetate (150mL). The aqueous layer was separated and extracted with ethyl acetatetwice. The organic solution was washed with water and a saturated NaClsolution was added. The solution was dried over Na₂SO₄, filtered andconcentrated. The resulting solid was triturated with ethanol to yield2-(Bis-methylsulfanyl-methylene)-5,6-dimethoxy-indan-1-one, IntermediateD, as a yellow solid. MS m/z 297 (M+H)⁺; ¹HNMR(CDCl₃): 2.50(s,3H),2.58(s, 3H), 3.80(s, 2H), 3.90(s, 3H), 4.0(s,3H), 7.20(s,1H),7.22(s,1H).

EXAMPLE 9

[1297](6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4-methoxy-phenyl)-amine,Compound 6 (Method D)

[1298] 50 mg (0.17 mmol) of intermediate D (prepared as described inExample 8 above), 25 mg of 4-methoxyaniline (0.2 mmol) and 1 mL ofacetic acid was placed in a reaction flask. The mixture was heated at70° C. overnight. The mixture was then poured into water and extractedwith ethyl acetate. The organic solution was washed, dried, andconcentrated to give a dark brown residue. The residue was suspended inethanol and mixed with 0.050 mL of hydrazine. The reaction mixture wasthen heated at 70° C. overnight, the mixture was diluted with ethylacetate and then washed with water, dried and concentrated. The crudeproduct was purified on a silica gel column using a mixture of methylenechloride and methanol as eluents. The pure fractions were collected andconcentrated to yield the title compound (Compound 6),(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4-methoxy-phenyl)-amine, as a brown solid. MS m/z 338 (M+H)⁺; HPLC:99% pure (uv);

[1299]¹HNMR (CDCl₃): 3.29(s,2H), 3.73(s,3H), 3.80(s,3H), 3.89(s,3H),6.80(d, 2H), 6.95(m,3H), 7.3(s,1H).

EXAMPLE 10

[1300] 3-Phenylamino-2H-indeno[1,2-c]pyrazol-4-one, Compound 35 (MethodE)

[1301] 1,3-indione (5 g, 0.0342 mol) and phenyl isothiocyanate, Compound1b, (4.1 mL, 0.0342 mol) were added into acetonitrile (50 mL) and cooledto 0° C. DBU (10.2 mL, 0.0684 mol) was then added dropwise and thereaction mixture was stirred at room temperature for two hours. Thereaction mixture was cooled to 0° C., then methyl iodide (3.2 mL, 0.051mol) was added slowly. The reaction mixture was stirred at roomtemperature for four hours, and then quenched with 50/50 aceticacid/water solution (300 mL). The precipitate was filtered and washedwith water.

[1302] The precipiate (0.50 g, 0.0017 mol), hydrazine (0.08 mL, 0.0026mol), and acetic acid (0.5 mL, 0.006 mol) were added together intoacetonitrile (10 mL) and then stirred at 75° C. for four hours. Thereaction mixture was quenched with saturated aq. NaHCO₃ solution,extracted with ethyl acetate, washed with brine, and dried over sodiumsulfate. The solvent was removed in vacuo. The resulting crude materialwas triturated with dichloromethane and methanol to yield the titlecompound (Compound 35) 3-Phenylamino-2H-indeno[1,2-c]pyrazol-4-one. MSm/z 262 (M+H)⁺; ¹HNMR (DMSO-d₆): 6.92(m,1H), 7.11(m,2H), 7.27(m,3H),7.48(m,3H) 9.60(s,1H), 12.3(s,1H).

EXAMPLE 11

[1303] 3-Phenylamino-2,4-dihydro-indeno[1,2-c]pyrazol-4-ol, Compound 50(Method E)

[1304] Compound 35, prepared as in Example 10, (0.15 g, 0.00057 mol) wassuspended in a mixture of 50/50 DCM/MeOH (50 mL), to which sodiumboronhydride (800 mg) was added. The reaction mixture was stirred for 2hours. The reaction mixture was then quenched with saturated aq. NaHCO₃solution, extracted with ethyl acetate, washed with brine, and driedover sodium sulfate. The solvent was removed in vacuo. The crudematerial was triturated with dichloromethane and methanol to yield thetitle compound, 3-Phenylamino-2,4-dihydro-indeno[1,2-c]pyrazol-4-ol. MSm/z 264 (M+H)⁺;

[1305]¹HNMR (DMSO-d₆): 5.28(m,2H), 6.70(m,1H), 7.19(m,6H), 7.34(m,1H),7.48(m,1H) 8.32(s,1H), 12.15(s,1H).

EXAMPLE 12

[1306] 5-Hydroxy-6-methoxy-indan-1-one, Intermediate H

[1307] A mixture of 5,6 dimethoxyindan-1-one (25.0 g, 0.13 mole),lithium chloride (20.0 g, 0.47 mole) and DMF (200.0 mL) was stirred at160° C. for 60 hrs. Water (400.0 mL) was added and the mixture washedwith ethyl acetate. The aqueous layer was acidified with 2N HCl andextracted with ethyl acetate (2×300.0 mL). The organic layer was washedwith brine and the solvent removed in vacuo. The crude material waspurified on a silica gel column using DCM/MeOH(97/3) as the eluent. Thesolvent was removed in vacuo to yield 5-hydroxy-6-methoxy-indan-1-one(Intermediate H) as a light yellow solid. MS m/z 179 (M+H)⁺: 179 m/z.The title compound (Intermediate H) is a known compound and may also beprepared by demethylation of 5,6 dimethyoxyindan-1-one using KCN/DMSO at100° C. (J. M. Saa et al., J. Org. Chem. 1992, 57, 589).

EXAMPLE 13

[1308] 5-(2,2-Dimethyl-1,3-dioxolan-4-ylmethoxy)-6-methoxy-indan-1-one,Intermediate I

[1309] A mixture of 5-Hydroxy-6-indan-1-one, Intermediate H, (0.50 g,0.0028 mol), 4-chloromethyl-2,2-dimethyl-1,3-dioxolane (0.766 mL, 0.0056mol), potassium carbonate (1.54 g, 0.011 mol) and DMF (20.0 mL) wasstirred at 95° C. for 3 days. Water (150.0 mL) was added and the mixturewas extracted with ethyl acetate (2×150 mL). The organic layer waswashed with sat. NaHCO₃, brine and dried over Na₂SO₄. The solvent wasthen removed in vacuo to yield5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6-methoxy-indan-1-one(Intermediate I) as light brown solid. MS m/z 293 (M+H)⁺.

EXAMPLE 14

[1310]3-[3-[(3-Chloro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol,Compound 259 (Method A)

[1311] A mixture of5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6-methoxy-indan-1-one(Intermediate I) (0.30 g, 0.001 mole), 3-chloro-phenyl isothiocyanate(Compound 14a) (0.14 mL, 0.0011 mole) and THF (1.5 mL) was added tolithium hexamethyldisilane (1.2 mL, 0.0012 mole) dropwise at roomtemperature with stirring. The reaction mixture was stirred for 4 hrs.Hydrazine (0.070 mL, 0.0022 mole) and acetic acid (0.132 mL, 0.0022mole) were added to the reaction mixture, which was then heated at thereflux temperature for 18 hrs. The resulting mixture was first added towater (10 mL) and then extracted with CH₂Cl₂. The organic layers werecombined and washed with aqueous NaHCO₃ solution, then washed with waterand brine solution, dried (Na₂SO₄), and the solvent was removed invacuo. The crude material was purified on the reverse phase HPLC andconverted to the desired product upon standing in the 0.1% TFA solution.Lyophilization yielded the title compound,3-[3-[(3-Chloro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diolas a white powder. MS m/z 402 (M+H)⁺; ¹HNMR (DMSO-d₆): 3.41(s, 2H),3.46(d, 2H), 3.78(s, 4H), 3.88(m,1H), 4.00(m,1H), 6.75(d, 1H), 7.15(m,4H), 7.40(s, 1H), 8.80(br s, 1H).

EXAMPLE 15

[1312] 5-(3-Bromo-propoxy)-6-methoxy-indan-1-one, Intermediate J

[1313] A mixture of 5-Hydroxy-6-methoxy-indan-1-one (Intermediate H)(5.0 g, 0.028 mole), 1,3-dibromopropane (5.7 mL, 0.056 mole) and sodiumhydride (1.2 g, 0.028 mole) were stirred in 50 mL of DMF at roomtemperature overnight under Argon. The reaction mixture was quenchedwith water (150 mL), extracted with ethyl acetate, then washed with 1NHCl and brine. The extract was dried over sodium sulfate and the solventremoved in vacuo to yield the title compound,5-(3-Bromo-propoxy)-6-methoxy-indan-1-one. MS m/z 297 (M+H)⁺.

EXAMPLE 16

[1314] 6-Methoxy-5-(3-pyrrolidin-1-yl-propoxy)-indan-1-one, IntermediateK

[1315] A mixture of 5-(3-bromo-propoxy)-6-methoxy-indan-1-one(Intermediate J) (2.0 g, 0.0066 mole) and pyrrolidine (1.7 mL, 0.02mole) was stirred in 50 mL of DME (1,2-Dimethoxyethane) at roomtemperature overnight under Argon. The reaction was quenched with water(150 mL) and made acidic with 1N HCl (50 mL). The water solution waswashed with ethyl acetate, made basic with 3N NaOH (25 mL) and extractedwith ethyl acetate. After washing with brine and drying over sodiumsulfate, the solvent was removed in vacuo to yield the title compound.MS m/z 290 (M+H)⁺.

EXAMPLE 17

[1316](3-Fluoro-phenyl)-[7-methoxy-6-(3-pyrrolidin-1-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine,Compound 180 (Method A)

[1317] A mixture of 6-methoxy-5-(3-pyrrolidin-1-yl-propoxy)-indan-1-one(Intermediate K, 0.45 g, 0.00155 mole), 3-fluoro-phenyl isothiocyanate(Compound 4a) (0.19 mL, 0.0017 mole) and THF (1.5 mL) was added tolithium hexamethyldisilane (1.8 mL, 0.0018 mole) dropwise at roomtemperature with stirring. The reaction mixture was stirred for 4 hrs.Hydrazine (0.095 mL, 0.003 mole) and acetic acid (0.180 mL, 0.003 mole)were added to the reaction mixture. The reaction mixture was then heatedat the reflux temperature for 18 hrs. The resulting mixture was firstadded to water (10 mL) and then extracted with CH₂Cl₂. The organiclayers were combined and washed with aqueous NaHCO₃ solution, thenwashed with water and brine solution, dried (Na₂SO₄), and solvent wasremoved in vacuo. The crude material was purified on the reverse phaseHPLC. Lyophilization yielded the title compound,(3-Fluoro-phenyl)-[7-methoxy-6-(3-pyrrolidin-1-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amineas a white powder. MS m/z 423 (M+H)⁺; ¹HNMR (DMSO-d₆): 1.88(m, 2H),2.00(m, 2H), 2.15(m, 2H), 3.02(m, 2H), 3.29(dd, 2H), 3.37(s, 2H),3.61(m, 2H), 3.74(s, 3H), 4.04(t, 2H), 6.52(t, 1H), 6.93(d, 1H), 7.18(m,4H), 8.8(br s, 1H), 9.7(br s, 1H).

EXAMPLE 18

[1318] 6-Methoxy-5-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-indan-1-one,Intermediate L

[1319] A mixture of 5-Hydroxy-6-methoxy-indan-1-one (Intermediate H,2.98 g, 0.017 mole), 2-(3-chloro-propoxy)-tetrahydro-pyran (Compound18a) (6.0 g, 0.034 mole), and potassium carbonate (10.0 g, 0.0725 mole)were stirred in 50 mL of DMF at 80° C. overnight under Argon. Thereaction mixture was then diluted with 200 mL of ethyl acetate andwashed 3 times with water. After drying over sodium sulfate, the solventwas removed in vacuo. The crude material solidified on standing to yieldthe title compound,6-Methoxy-5-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-indan-1-one. MS m/z309 (M+H)⁺.

EXAMPLE 19

[1320]3-[7-Mehoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol,Compound 266 (Method A)

[1321] A mixture of6-methoxy-5-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-indan-1-one(Intermediate L) (0.16 g, 0.0005 mole), 3-methoxy-phenyl isothiocyanate(Compound 19a) (0.08 mL, 0.0006 mole) and THF (1.5 mL) was added tolithium hexamethyldisilane (0.7 mL, 0.0007 mole) dropwise at roomtemperature with stirring. The reaction mixture was stirred for 4 hrs.Hydrazine (0.035 mL, 0.0011 mole) and acetic acid (0.66 mL, 0.0011 mole)were added to the reaction mixture, which was then heated at the refluxtemperature for 18 hrs. To the resulting mixture was first added water(10 mL) and then the reaction mixture was extracted with CH₂Cl₂. Theorganic layers were combined and washed with aqueous NaHCO₃ solution,then washed with water and brine solution, dried (Na₂SO₄), and solventwas removed in vacuo. The crude material was purified on the reversephase HPLC and converted to the desired product upon standing in the 1%TFA in CH₃CN: water solution. Lyophilization yielded the title compound,3-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-olas a white powder. MS m/z 382 (M+H)⁺; ¹HNMR (DMSO-d₆): 1.88(m, 2H),3.40(s, 2H), 3.57(t, 2H), 3.72(s, 3H), 3.78(s, 3H), 4.05(t, 2H), 6.38(d,1H), 6.68(d, 1H), 6.77(s, 1H), 7.10(m, 2H), 7.25(s, 1H), 8.75(br s, 1H).

EXAMPLE 20

[1322] 6-Methoxy-5-oxiranylmethoxy-indan-1-one, Intermediate M

[1323] A mixture of 5-Hydroxy-6-methoxy-indan-1-one (Intermediate H, 5.0g, 0.028 mole), 2-chloromethyl-oxirane (4.4 mL, 0.056 mole), andpotassium carbonate (11.6 g, 0.084 mole) was stirred in 50 mL of DMF at70° C. overnight under Argon. The reaction was then diluted with 200 mLof ethyl acetate and washed 3 times with water. The ethyl acetatesolution was dried over sodium sulfate and the solvent removed in vacuoto yield the title compound (Intermediate M). MS m/z 236 (M+H)⁺.

EXAMPLE 21

[1324] 5-(2-Hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-indan-1-one,Intermediate N

[1325] A mixture of 6-methoxy-5-oxiranylmethoxy-indan-1-one(Intermediate M, 2.5 g, 0.0106 mole) and pyrrolidine (0.9 mL, 0.011mole) was stirred in 50 mL of DME at 50° C. for 5 hrs under Argon. Then,150 mL of ethyl acetate was added and the solution washed with water(2×). Following extraction with 2N HCl, the aqueous acidic layer wasmade basic with 3N NaOH and extracted with ethyl acetate. The ethylacetate extracts were washed with brine, dried over sodium sulfate andthe solvent removed in vacuo. The resulting residue was triturated withdiethyl ether to yield the title compound. MS m/z 306 (M+H)⁺.

EXAMPLE 22

[1326]1-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol,Compound 270 (Method A)

[1327] To a mixture of5-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-indan-1-one(Intermediate N) (0.16 g, 0.0005 mole), 3-methoxy-phenyl isothiocyanate(Compound 19a) (0.08 mL, 0.0006 mole) and THF (1.5 mL) was added tolithium hexamethyldisilane (0.7 mL, 0.0007 mole) dropwise at roomtemperature with stirring. The reaction mixture was stirred for 4 hrs.Hydrazine (0.035 mL, 0.0011 mole) and acetic acid (0.66 mL, 0.0011 mole)were added to the reaction mixture. The reaction mixture was then heatedat the reflux temperature for 18 hrs. To the resulting mixture was firstadded water (10 mL) and then the reaction mixture was extracted withCH₂Cl₂. The organic layers were combined and washed with aqueous NaHCO₃solution, then washed with water and brine solution, dried (Na₂SO₄), andsolvent was removed in vacuo. The crude material was purified by reversephase HPLC. Lyophilization yielded the title compound,1-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-olas a white powder. MS m/z 451 (M+H)⁺; ¹HNMR (DMSO-d₆): 1.89(m, 2H),2.02(m, 2H), 3.12(m, 2H), 3.34(m, 2H), 3.45(s, 2H), 3.62(s, 2H), 3.70(s,3H), 3.85(s, 3H), 4.00(m, 2H), 4.20(m, 2H), 6.37(d, 1H), 6.71(d, 1H),6.78(s, 1H), 7.10(t, 1H), 7.25(s, 1H), 7.3(s,1H), 8.68(br s, 1H),9.60(br s, 1H).

EXAMPLE 23

[1328] 5,6-Dihydroxy-indan-1-one, Intermediate O

[1329] A solution of 5,6-dimethoxyindan-1-one (Compound 3a) (19 g, 0.094mole) in 200 mL of methylene chloride was cooled at −78° C. with adry-ice/iPrOH bath. To this solution was then added 200 mL (0.2 mole) ofa 1M solution of BBr₃ in CH₂Cl₂ dropwise. The resulting solution wasstirred at −78° C. for 1 hr and then at 0° C. for 1 hr. The solution wasthen cooled back to −78° C. with a dry-ice/iPrOH bath and quenched with50 mL of MeOH. The solution was evaporated on a rotary evaporator todryness, the solid was re-dissolved in MeOH and concentrated again fortwo more times. The red solid, the title compound, was used insubsequent reactions without further purification. MS m/z 165 (M+H)⁺.

EXAMPLE 24

[1330] 5,6-Diethoxy-indan-1-one, Intermediate P

[1331] A mixture of 5,6-dihydroxy-indan-1-one (Intermediate O) (24 g,0.146 mole), potassium carbonate (60 g, 0.43 mole) and diethyl bromide(56 mL, 0.75 mole) in DMF (200 mL) was stirred at 60° C. for 14 hrs.Water (150 mL) was added to the reaction and the reaction mixture wasthen extracted with ethyl acetate (2×150 mL). The ethyl acetate extractswere washed with saturated NaHCO₃, brine and dried over Na₂SO₄. Thesolvent was then removed in vacuo to yield the title compound as a brownsolid. MS m/z 221 (M+H)⁺.

EXAMPLE 26

[1332]4-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-4-oxo-butyricacid methyl ester, Compound 428 (Method M)

[1333] To a mixture of(6,7-Dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine(Compound 14) (0.50 g, 1.5 mmol), 3-Chlorocarbonyl-propionic acid methylester (Compound 26a) (0.277 g, 1.8 mmole) and DMF (1.5 mL) was addedDiisopropylethylamine (DIEA) (0.52 mL, 3.0 mmole) at room temperaturewith stirring. The reaction was stirred at room temperature over night.The reaction was quenched with water and extracted with EtOAc. Thesolvent was removed via rotovap and the crude material was prepped onthe reverse phase HPLC. Lyophilization gave the title compound as awhite powder. MS m/z439.9 (M+H)⁺;

[1334]¹HNMR (DMSO-d₆): 2.78(t, 2H), 3.32(t, 2H), 3.45(s, 2H), 3.62(s,3H), 3.79(s, 6H), 6.64(m, 1H), 7.15(s, 1H), 7.30(m, 2H), 7.62(d, 1H),7.70(s, 1H), 9.45(s, 1H).

EXAMPLE 27

[1335]1-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-2-hydroxy-ethanone,Compound 432 (Method M)

[1336] To a mixture of(6,7-Dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine(Compound 14) (3.6 g, 10.0 mmol), Benzyloxy-acetyl chloride (Compound27a) (2.2 g, 12.0 mmole) and DMF (50 mL) was added Diisopropylethylamine(5.2 mL, 30 mmole) at room temperature with stirring. The reaction wasstirred at room temperature over night. The reaction was quenched withwater and extracted with EtOAc. Dried over sodium sulfate and removedsolvent in vacuo. The crude material was then taken up into ethanol and0.5 g of Pd/C was added. The reaction was shaken on the hydrogenatorover night. The reaction was filtered through Celite and removed solventin vacuo. Triturated in a small amount of EtOAc. 3.2 g of ˜90% purematerial was produced. 300 mg of the crude material was prepped on theGilson and lyophilization gave Compound 432 as a white powder. MS m/z384 (M+H)⁺;

[1337]¹HNMR (DMSO-d₆): 3.55(s, 2H), 3.82(s, 6H), 4.87(s, 2H), 5.40(br s,1H), 6.65(m, 1H), 7.24(m, 3H), 7.58(d, 1H), 7.92(s,1H), 9.50(s,1H).

EXAMPLE 28

[1338]1-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-3-pyrrolidin-1-yl-propane-1,3-dione,Compound 536 (Method N)

[1339] A mixture of(6,7-Dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine(Compound 14) (0.36, 1.0 mmol), 3-Oxo-3-pyrrolidin-1-yl-propionic acid(Compound 28a) (0.157 g, 1.0 mmole),1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.24 g, 1.25 mmol),hydroxybenzo-triazole hydrate (HOBT) (0.17 g, 1.25 mmol) and DIEA (0.220mL, 1.25 mmol) was stirred in 10 mL DMF over night at room temperature.The reaction was quenched with saturated NaHCO₃ and extracted withEtOAc. The solvent was removed in vacuo and the crude material wasprepped on the Gilson. Lyophilization produced a white powder. MS m/z465.1 (M+H)⁺;

[1340]¹HNMR (DMSO-d₆): 1.82(m, 2H), 1.98(m, 2H), 3.34(s, 2H), 3.59(m,4H), 3.79(s, 3H), 3.80(s, 3H), 4.09(s, 2H), 6.67(t,1H), 7.27(m 3H),7.65(d,1H), 8.89(s, 1H), 9.50(s, 1H).

EXAMPLE 29

[1341]1-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-2-yl]-3-pyrrolidin-1-yl-propane-1,3-dione,Compound 535 (Method N)

[1342] A mixture of(6,7-Dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine(Compound 14) (0.36, 1.0 mmol), 3-Oxo-3-pyrrolidin-1-yl-propionic acid(Compound 28a) (0.157 g, 1.0 mmole), EDC (0.24 g, 1.25 mmol), HOBt (0.17g, 1.25 mmol), and DIEA (0.220 mL, 1.25 mmol) was stirred in 10 mL DMFover night at room temperature. The reaction was quenched with saturatedNaHCO₃ and extracted with EtOAc. The solvent was removed in vacuo andthe crude material was prepped on the Gilson. Lyophilization producedCompound 535 as a white powder. MS m/z 465.1 (M+H)⁺;

[1343]¹HNMR (DMSO-d₆): 1.82(m, 2H), 1.98(m, 2H), 3.34(s, 2H), 3.59(m,4H), 3.79(s, 3H), 3.80(s, 3H), 4.09(s, 2H), 6.67(t,1H), 7.27(m 3H),7.65(d, 1H), 8.89(s, 1H), 9.50(s,1H).

EXAMPLE 30

[1344] 5-Hydroxy-6-methoxy-4-nitro-indan-1-one, Intermediate Q

[1345] The intermediate H was a known compound and was preparedaccording to the literature procedure described in Jose M. saa, etal J.Org Chem., 57(2), 589, 1992. 5-Hydroxy-6-methoxy-indan-1-one(Intermediate H) (3.0 g. 0.017 mol) was taken into 100 mL diethyl etherand 7.5 mL of nitric acid was added dropwise. The reaction stirred atroom temperature for two hours. The reaction was complete by HPLC. Theprecipitate was filtered off and washed with ether. 3.2 g of a yellowsolid (Intermediate Q) was produced. MS m/z 224 (M+H)⁺;

[1346]¹HNMR (DMSO-d₆): 2.64(m, 2H), 3.15(m, 2H), 3.92(s, 3H), 7.32(s,1H), 11.75(s, 1H).

EXAMPLE 31

[1347] 4-Amino-5-hydroxy-6-methoxy-indan-1-one, Intermediate R

[1348] The intermediate Q was a known compound and was preparedaccording to the literature procedure described in Jose M. saa, etal J.Org Chem., 57(2), 589, 1992. 5-Hydroxy-6-methoxy-4-nitro-indan-1-one(Intermediate Q) (2.0 g, 9.0 mmol) was added to the tinchloridedihydrate (10.0 g, 44 mmol) in 30 mL conc. HCl over an ice bath. Thereaction stirred at room temperature overnight. The reaction wascomplete by HPLC. The reaction was quenched with water and made neutralwith solid NaOH pellets. The solid precipitate that formed was filteredoff through Celite. The aqueous layer was extracted with EtOAc, washedwith brine, and dried over sodium sulfate. The solvent was removed viarotovap to produce 1.5 g of Intermediate R as a yellow solid. MS m/z 194(M+H)⁺;

[1349]¹HNMR (DMSO-d₆): 2.42(m, 2H), 2.76(m, 2H), 3.71(s, 3H), 6.50(s,1H).

EXAMPLE 32

[1350] 4-Methoxy-2-methyl-7,8-dihydro-indeno[4,5d]oxazol-6-one,Intermediate S

[1351] The intermediate R was a known compound and was preparedaccording to the literature procedure described in Jose M. saa, etal J.Org Chem., 57(2), 589, 1992. 4-Amino-5-hydroxy-6-methoxy-indan-1-one(Intermediate R) (1.5 g, 7.8 mmol) was taken into 40 mL of glacialacetic acid and gently refluxed overnight. Reaction not complete by HPLCso the reaction was continued for one more day. Quenched with water,made basic with 3N NaOH and extracted with EtOAc. Washed with brine,dried over Na₂SO₄ and removed solvent in vacuo. 1.2 g of a dark solid(Intermediate Q) was produced; MS m/z 218 (M+H)⁺.

EXAMPLE 33

[1352](3-Fluoro-phenyl)-(4-methoxy-2-methyl-7,9-dihydro-3-oxa-1,6,7-triaza-cyclopenta[b]-as-indacen-8-yl)-amine,Compound 605 (Method A)

[1353] A mixture of4-Methoxy-2-methyl-7,8-dihydro-indeno[4,5-d]oxazol-6-one (Compound 33a)(0.22 g, 0.001 mole), 3-fluoro-phenyl isothiocyanate (Compound 4a) (0.14mL, 0.0011 mole) and THF (1.5 mL) was added to lithiumhexamethyldisilane (1.2 mL, 0.0012 mole) dropwise at room temperaturewith stirring. The reaction mixture was stirred for 4 hrs to provide anintermediate product (Compound 33b) which was not isolated. Hydrazine(0.070 mL, 0.0022 mole) and acetic acid (0.132 mL, 0.0022 mole) wereadded to the reaction mixture, which was then heated at the refluxtemperature for 18 hrs. The resulting mixture was first added to water(10 mL) and then extracted with EtOAc. The organic layers were combinedand washed with aqueous NaHCO₃ solution, then washed with water andbrine solution, dried (Na₂SO₄), and solvent was removed in vacuo. Thecrude material was prepped on the reverse phase HPLC. Lyophilizationproduced Compound 605 as a white powder. MS m/z 351.1 (M+H)⁺;

[1354]¹HNMR (DMSO-d₆): 2.62(s, 3H), 3.60(s, 2H), 4.05(s, 3H), 6.54(t,1H), 6.98(d, 1H), 7.22(m, 3H), 8.87(br, 1H).

EXAMPLE 34

[1355] 5,6-Dimethoxy-4-nitro-indan-1-one, Intermediate T

[1356] 5-Hydroxy-6-methoxy-4-nitro-indan-1-one (Intermediate Q) (4.4 g,0.02 mol) and potassium carbonate (2.7 g, 0.02 mol) were taken up intoDMF. Methyl iodide (5.0 mL, 0.08 mol) was added and the reaction stirredat room temperature overnight. Only 15% conversion by HPLC so thereaction was continued for 4 more days at 50° C. Quenched the reactionwith water and extracted with EtOAc. Washed with brine, dried overNa₂SO₄ and removed solvent in vacuo. 3.4 g of crude material(Intermediate T) was produced. MS m/z 238 (M+H)⁺.

EXAMPLE 35

[1357] 4-Amino-5,6-dimethoxy-indan-1-one, Intermediate U

[1358] 5,6-Dimethoxy-4-nitro-indan-1-one (Intermediate T) (2.0 g, 8.4mmol) was added to the tinchloride dihydrate(10.0 g, 44 mmol) in 30 mLconc. HCl over an ice bath. The reaction stirred at room temperatureovernight. The reaction was complete by HPLC. The reaction was quenchedwith water and made neutral with solid NaOH pellets. The solidprecipitate that formed was filtered off through Celite. The aqueouslayer was extracted with EtOAc, washed with brine, and dried over sodiumsulfate. The solvent was removed via rotovap to produce 1.2 g of yellowsolid (Intermediate U). MS m/z 208 (M+H)⁺;

[1359]¹HNMR (CDCl₃): 2.69(m, 2H), 2.80(m, 2H), 3.84(s, 3H), 3.87(s, 3H),4.02(s, 2H), 6.72(s, 1H).

EXAMPLE 36

[1360] N-(5,6-Dimethoxy-1-oxo-indan-4-yl)-acetamide, Intermediate V

[1361] 4-Amino-5,6-dimethoxy-indan-1-one (Intermediate U) (0.214 g, 1.0mmol) was taken up into 5 mL of DMF and acetyl chloride (0.071 mL, 1.0mmol) and DIEA (0.18 mL, 1.0 mmol) were added. The reaction stirredovernight at room temperature. The reaction was quenched with sat.sodium bicarbonate and extracted with EtOAc. The organic layer waswashed with brine, dried over Na2SO4 and removed in vacuo. 0.25 g of thecrude material was produced (Intermediate V); MS m/z 250.1 (M+H)⁺.

EXAMPLE 37

[1362]N-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-5-yl]-acetamide,Compound 557 (Method A)

[1363] A mixture of N-(5,6-Dimethoxy-1-oxo-indan-4-yl)-acetamide(Intermediate V) (0.25 g, 0.001 mole), 3-fluoro-phenyl isothiocyanate(Compound 4a) (0.14 mL, 0.0011 mole) and THF (1.5 mL) was added tolithium hexamethyldisilane (1.2 mL, 0.0012 mole) dropwise at roomtemperature with stirring. The reaction mixture was stirred for 4 hrs toprovide an intermediate product (Compound 37a) which was not isolated.Hydrazine (0.070 mL, 0.0022 mole) and acetic acid (0.132 mL, 0.0022mole) were added to the reaction mixture then it was heated at thereflux temperature for 18 hrs. The resulting mixture was first addedwater (10 mL) and then extracted with EtOAc. The organic layers werecombined and washed with aqueous NaHCO₃ solution, then washed with waterand brine solution, dried (Na₂SO₄), and solvent was removed in vacuo.The crude material was prepped on the reverse phase HPLC. Lyophilizationgave a white powder (Compound 557). MS m/z 383.1 (M+H)⁺;

[1364]¹HNMR (DMSO-d₆): 2.07(s,1H), 3.32(s, 1H), 3.40(s, 1H), 3.72(s,3H), 3.89(s, 3H), 6.51(t, 1H), 6.92(t, 1H), 7.18(m, 3H), 8.87(br, 1H),9.62(s, 1H).

EXAMPLE 38

[1365]3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazole-1-carboxylicacid isopropyl ester, Compound 436 (Method O)

[1366] A solution of(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amineHCl (Compound 14) (0.50 g, 0.0014 mole), THF (10 mL), and Diisopropylamine (0.512 mL, 0.00295 mole) was stirred until the solid completelydissolved. Isopropyl chloroformate (1.5 mL, 0.0015 mole) was addedslowly at room temperature. The reaction mixture was stirred at roomtemperature overnight. The solvent was removed in vacuo from theresulting organics. Attempt to separate resulting isomers withreverse-phase chromatography was not successful. Placed isomercontaining fractions in refrigerator. Much of major isomer crystallized.Filtered white crystals of title compound from solution (Compound 436).MS m/z 412 (M+H)⁺;

[1367]¹HNMR (DMSO-d₆): 1.4 (d, 6H), 3.55 (s, 2H), 3.85 (s, 6H), 5.25(sept, 1H), 6.65 (t, 1H), 7.25 (m, 3H), 7.65 (d, 1H), 7.8 (s, 1H), 9.4(s, 1H).

EXAMPLE 39

[1368]3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazole-1-carboxylicacid 2-methoxy-ethyl ester, Compound 438 (Method O)

[1369] A solution of(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amineHCl (Compound 14) (0.50 g, 0.0014 mole), THF (10 mL), and Diisopropylamine (0.512 mL, 0.00295 mole) was stirred until the solid completelydissolved. 2-Methoxyethyl chloroformate (0.178 mL, 0.00154 mole) wasadded dropwise at room temperature. After 2 hours of stirring, reactionwas complete. Solvent was removed in vacuo and organic oil placed onreverse phase chromatography system for separation of the isomers.Separation was successful. Fractions were collected and lyophilized toyield a pale yellow solid (Compound 438). NMR showed the major isomer tobe the title compound. MS m/z 428 (M+H)⁺;

[1370]¹H NMR (DMSO-d₆): 3.35 (s, 3H), 3.6 (s, 2H), 3.75 (t, 2H), 3.85(d, 6H), 4.6 (t, 2H), 6.7 (m, 1H), 7.3 (m, 3H), 7.7 (d, 1H), 7.8 (s,1H), 9.4 (s, 1H).

EXAMPLE 40

[1371]3-(3-Fluoro-phenyl-amino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazole-2-carboxylicacid 2-methoxy-ethyl ester, Compound 437 (Method O)

[1372] A solution of(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amineHCl (Compound 14) (0.50 g, 0.0014 mole), THF (10 mL), and Diisopropylamine (0.512 mL, 0.00295 mole) was stirred until the solid completelydissolved. 2-Methoxyethyl chloroformate (0.178 mL, 0.00154 mole) wasadded dropwise at room temperature. After 2 hours of stirring, reactionwas complete. Solvent was removed in vacuo and organic oil placed onreverse phase chromatography system for separation of the isomers.Separation was successful. Fractions were collected and lyophilized toyield a pale yellow solid (Compound 437). NMR showed the minor isomer tobe the title compound. MS m/z 428 (M+H)⁺;

[1373]¹H NMR (DMSO-d₆): 3.35 (s, 3H), 3.4 (s, 2H), 3.7 (t, 2H), 3.8 (s,3H), 3.9(s, 3H), 4.5 (t, 2H), 6.85 (t, 1H), 7.0 (m, 2H), 7.2 (s, 1H),7.35 (m, 2H), 8.9 (s, 1H).

EXAMPLE 41

[1374]3-(3-Fluoro-phenyl-amino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazole-1-carboxylicacid 2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethyl ester, Compound 471 (MethodO)

[1375] Two flasks were set up containing 50 mL of THF in each. Added(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amineHCl (Compound 14) (0.50 g, 0.0014 mole) and diisopropyl amine (0.512 mL,0.00295 mole) to the first flask which was stirred under argon until thesolid completely dissolved. Tri(ethyleneglycol) bis(chloroformate)(1.134 mL, 0.0055 mole) was added to the second flask and placed in dryice/isopropyl alcohol bath under argon. The first flask was then addedall at once to the second flask. Reaction was complete within 10minutes. The reaction was allowed to come to room temperature. Solventwas removed in vacuo. The resulting brown oil was taken up in ethylacetate and dichloromethane and washed with sodium bicarbonate. Theresulting organics were dried (sodium sulfate), filtered, and thesolvent was removed in vacuo. The major isomer (Compound 471) wasseparated from the minor by reverse phase chromatography. By ¹H NMR, thefree chloroformate had hydrolyzed to the alcohol in the DMSO used toload the reverse phase column. Fractions of each isomer were collectedand lyophilized. MS m/z 502 (M+H)⁺;

[1376]¹H NMR (DMSO-d₆): 3.3-3.7 (m, 12H), 3.85 (d, 6H), 4.6 (m, 2H), 6.7(m, 1H), 7.3 (m, 3H), 7.7 (d, 1H), 7.8 (s, 1H), 9.4 (s, 1H).

EXAMPLE 42

[1377](6,7-dimethoxy-1-methyl-1,4-dihydro-indeno[1,2-c]pyrazole-3-yl)-(3-fluoro-phenyl-amine,Compound 609 (Method L)

[1378] Iodomethane (0.141 g, 0.001 mole) was added to a mixture of(3-Fluoro-phenyl)-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]1-N-methyl-pyrazol-3-yl)-amine(Compound 14) (321 mg, 0.001 mole), diisopropylethylamine (0.129 g,0.001 mole), and DCM (5 mL). The reaction mixture was stirred at roomtemperature with stirring for 18 hrs. The resulting mixture was firstadded to water (5 mL) and then extracted with CH₂Cl₂. the organic layerswere combined and washed with aqueous NaHCO₃ solution, then wash withwater, dried over (Na₂SO₄), and solvent was removed in vacuum. Themixture contained two isomers based on hplc/ms analysis. The mixture wasseparated by HPLC with C-18 reversed phase column and CH₃CN—H₂O-TFA asgradient solvent. The title compound (Compound 609; major isomer) wasobtained as a solid TFA salt.

[1379] HPLC: 100% (uv 214 mμ); MS m/z 340 (M+H)⁺;

[1380]¹HNMR (CDCl₃-d₁): 3.33 (s, 2H), 3.84 (s, 3H), 3.90 (s, 3H), 3.95(s, 3H), 6.48 (t, 1H), 6.66 (d, 1H), 6.57 (d, 1H), 7.0 (s, 1H), 7.1 (t,2H).

EXAMPLE 43

[1381](6,7-dimethoxy-2-methyl-1,4-dihydro-indeno[1,2-c]pyrazole-3-yl)-(3-fluoro-phenyl)-amine,Compound 610 (Method L)

[1382] Iodomethane (0.141 g, 0.001 mole) was added to a mixture of(3-Fluoro-phenyl)-6,7-dimethoxy-2,4-dihydro-indeno [1,2-c]1-N-methyl-pyrazol-3-yl)-amine (Compound 14) (321 mg, 0.001 mole),diisopropylethylamine (0.129 g, 0.001 mole), and DCM (5 mL). Thereaction mixture was stirred at room temperature with stirring for 18hrs. The resulting mixture was first added to water (5 mL) and thenextracted with CH₂Cl₂. the organic layers were combined and washed withaqueous NaHCO₃ solution, then wash with water, dried over (Na₂SO₄), andsolvent was removed in vacuum. The mixture contained two isomers basedon hplc/ms analysis. The mixture was separated by HPLC with C-18reversed phase column and CH₃CN—H₂O-TFA as gradient solvent. The titlecompound (Compound 610; minor isomer) was obtained as a solid TFA salt.MS m/z 340 (M+H)⁺;

[1383]¹HNMR (CDCl₃-d₁): 3.33 (s, 2H), 3.74 (s, 3H), 3.84 (s, 3H), 3.88(s, 3H),6.37 (d, 1H), 6.46 (d, 1H), 6.53 (t, 1H), 7.0 (s, 1H), 7.1 (t,1H), 7.2 (s, 1H).

EXAMPLE 44

[1384]3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazole-2-carboxylicacid (3-fluoro-phenyl)-amide, Compound 395 (Method Q)

[1385] To a mixture of(3-Fluoro-phenyl)-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]1-N-methyl-pyrazol-3-yl)-amine(Compound 14) (321 mg, 0.001 mole), diisopropylethylamine (0.129 g,0.001 mole), and DCM (5 mL) was added 3-fluorophenylisocyanate (Compound44a) (0.137 g 0.001 mole). The reaction mixture was stirred at roomtemperature with stirring for 18 hrs. The resulting mixture was firstadded to water (5 mL) and then extracted with CH₂Cl₂. the organic layerswere combined and washed with aqueous NaHCO₃ solution, then wash withwater, dried over (Na₂SO₄), and solvent was removed in vacuum. The titlecompound was purified by HPLC with C-18 reversed phase column andCH₃CN—H₂O-TFA as gradient solvent. The title compound was obtained as asolid TFA salt. MS m/z 463 (M+H)⁺;

[1386]¹HNMR (CDCl₃-d₁): 3.33 (s, 2H), 3.74 (s, 3H), 3.84 (s, 3H), 3.88(s, 3H),6.377 (m, 1H), 7.21 (s 1H), 7.33 (m, 3H),7.4 (m, 2H), 7.6 (d,1H), 7.85 (s, 1H), 7.9 (m, 1H), 9.31 (s, 1H), 9.54 (s, 1H).

EXAMPLE 46

[1387](2-Chloro-pyrid-3-yl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine,Compound 377 (Method B)

[1388] To a solution of2-(Imidazole-1-carbothioyl)-5,6-dimethoxy-indan-1-one (Intermediate B)(0.302 g, 0.001 mole) (prepared as in example 5), was mixed with3-amino-2-chloropyridine (Compound 46a) (0.128 g, 0.001 mole) and 10 mLTHF in a flask. 5,6-Dimethoxy-1-oxo-indan-2-carbothioic acid(4-chloro-N-methyl-phenyl)-amide (Compound 46b) was obtained afterstirring the reaction mixture for 4 hrs at room temperature as shown byHPLC/MS, HPLC/MS m/z 362 (M+H)⁺.

[1389] The intermediate (Compound 46b) was not isolated and the mixturewas subsequently treated with hydrazine (0.04 mL, 1.3 mmol), and aceticacid (2 drops). The reaction was heated at 75° C. for 18 hrs. Thereaction solution was then diluted with CH₂Cl₂, and washed with aqueousNaHCO₃ solution, then wash with water, dried over (Na₂SO₄), and solventwas removed in vacuum. The title compound was purified by HPLC with C-18reversed phase column and CH₃CN—H₂O-TFA as gradient solvent. The titlecompound (Compound 529) was obtained as a solid TFA salt. MS m/z 343(M+H)⁺;

[1390]¹HNMR (CDCl₃-d₁): 3.33 (s, 2H), 3.84 (s, 3H), 3.88 (s, 3H), 6.77(t, 1H), 6.86 (d 1H), 7.6 (d, 1H), 7.9 (d, 1H), 8.23 (s, 1H).

EXAMPLE 47

[1391] 5,6-Dimethoxy-3-ethyl-indan-1-one, Intermediate W

[1392] A mixture of 1,2-dimethoxy-benzene (Compound 47a) (21.9 mL, 0.170mole) and pent-3-enoic acid (Compound 47b) (25.5 g, 0.255 mole) wasstirred under argon in an ice bath. Polyphosphoric acid (230 g, 1.05mole) was added slowly. After addition was complete, the ice bath wasremoved and the reaction heated for 16 hours at 60° C. The reaction wasadded to ice water and extracted with dichloromethane. The organicextracts were washed with 3N NaOH, water, brine and dried over Na₂SO₄.The solvent was then removed in vacuo to yield a red oil containing thecrude title compound. The crude material was purified on a silica gelcolumn using dichloromethane as eluent. The pure fractions were combinedand concentrated to yield the racemic mixture of the title compound asan off-white solid. MS m/z 221 (M+H)⁺;

[1393] HPLC: 99% pure (UV);

[1394]¹HNMR: 0.9 (t, 3H), 1.4 (m, 1H), 2.0 (m, 1H), 2.2 (d of d, 1H),2.7 (d of d, 1H), 3.2 (m, 1H), 3.8 (s, 1H), 3.9 (s, 1H), 7.0 (s, 1H),7.2 (s, 1H).

EXAMPLE 48

[1395] *R-5,6-Dimethoxy-3-ethyl-indan-1-one, Intermediate W(*R);*S-5,6-Dimethoxy-3-ethyl-indan-1-one, Intermediate W(*S)

[1396] The racemic mixture, prepared in Example 47, was for chiralseparation. The separation was done on a ChiralpackAD column (500 g, 5cm ID and 41 cm length) using hexane/ethanol:88/12 isocratically as theeluent. The pure enantiomers were collected and solvent removed in vacuoto yield off white crystals of the title compounds. MS m/z 221 (M+H)⁺;

[1397] HPLC: 99% pure (UV);

[1398]¹HNMR: 0.9 (t, 3H), 1.4 (m, 1H), 2.0 (m, 1H), 2.2 (d of d, 1H),2.7 (d of d, 1H), 3.2 (m, 1H), 3.8 (s, 1H), 3.9 (s, 1H), 7.0 (s, 1H),7.2 (s, 1H).

[1399] *R and *S configurations are as drawn. The absoluteconfigurations are not determined.

[1400] *R isomer has rotation: α(MeOH)=−20.55

[1401] *S isomer has rotation: α(MeOH)=+18.60

EXAMPLE 49

[1402] 5,6-Dimethoxy-3-methyl-indan-1-one, Intermediate X

[1403] A mixture of 1,2-dimethoxy-benzene (Compound 47a) (19.1 mL, 0.150mole) and but-3-enoic acid (Compound 49a) (19.2 mL, 0.225 mole) wasstirred under argon in an ice bath. Polyphosphoric acid (230 g, 1.05mole) was added slowly. After addition was complete, the ice bath wasremoved and the reaction heated for 16 hours at 60° C. The reaction wasadded to ice water and extracted with ether. The organic extracts werewashed with 3N NaOH, water, brine and dried over Na₂SO₄. The solvent wasthen removed in vacuo to yield a yellow solid containing a racemicmixture of the title compounds. The crude material was purified on asilica gel column using 1:2 EtOAc:hexane as the eluents. The purefractions were combined and concentrated to yield the racemic mixture ofthe title compound (Intermediate X) as an off-white solid.

[1404] MS m/z 207 (M+H)⁺;

[1405]¹HNMR: 1.3 (d, 3H), 2.1 (d of d,1H), 2.8 (d of d, 1H), 3.3 (m,1H), 3.8 (s, 3H), 3.9 (s, 3H), 7.0 (s, 1H), 7.2 (s, 1H).

EXAMPLE 50

[1406] (3R)-(5,6-dimethoxy-3-methyl)-indan-1-one, Intermediate X(*R);(3S)-(5,6-dimethoxy-3-methyl)-indan-1-one, Intermediate X(*S)

[1407] The racemic mixture (Intermediate X), prepared in Example 49, wasfor chiral separation. The separation was done on a Chiralpack AD column(500 g, 5 cm ID and 41 cm length) using hexane/ethanol:88/12isocratically as the eluent. The pure enantiomers were collected andsolvent removed in vacuo to yield off white crystals of the titlecompound. MS m/z 207 (M+H)⁺; HPLC: 97% pure (UV);

[1408]¹HNMR: 1.3 (d, 3H), 2.1 (d of d, 1H), 2.8 (d of d, 1H), 3.3 (m,1H), 3.8 (s, 3H), 3.9 (s, 3H), 7.0 (s, 1H), 7.2 (s, 1H).

[1409] *R and *S configurations are as drawn. The absoluteconfigurations are not determined.

[1410] *R isomer has rotation: α(MeOH)=−5.85

[1411] *S isomer has rotation: α(MeOH)=+6.00

EXAMPLE 51

[1412](4R)-N-(3-bromo-phenyl)-(6,7-dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amineCompound 553 (Method A)

[1413] *R-5,6-Dimethoxy-3-methyl-indan-1-one (Intermediate X(*R)) (0.250g, 0.0012 mole) was added to a flask under argon and stirred in THFuntil dissolved. Lithium hexamethyldisilane (1.22 mL, 0.00122 mole) wasadded dropwise. The solution stirred for 30 minutes until it turned deepred. 3-Br-isothiocyanate (Compound 51a) (0.261 g, 0.00122 mole) wasadded and the reaction became deeper red. Acetic acid (0.076 mL, 0.00132mole) and hydrazine hydrate (0.059 mL, 0.00122 mole) were added. Thereaction was refluxed at 80° C. for 18 hours. Upon completion, 1 mL ofwater was added to the reaction. The solution was poured over a dryingcolumn and extracted from the column using dichloromethane. The solventwas blown off with nitrogen gas and the crude material dissolved in DMSOfor purification on reverse phase HPLC. The pure fractions werecollected and lyophilized to yield the title compound (Compound 553) asa pale yellow solid. MS m/z 401 (M+H)⁺;

[1414] HPLC: 100% pure (UV)

[1415]¹HNMR: 1.2(d, 3H), 3.7(q, 1H), 3.8(d, 6H), 7.0(m, 1H), 7.1(s, 1H),7.2(d,2H), 7.25(s, 1H), 7.55(s, 1H), 8.8(s, 1H).

[1416] *R isomer has rotation: α(MeOH)=+62.85

[1417] The absolute configuration has not been determined.

EXAMPLE 52

[1418]*S-(3-Bromo-phenyl)-(6,7-dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine,Compound 568 (Method A)

[1419] *S-5,6-Dimethoxy-3-methyl-indan-1-one (Intermediate X(*S)) (0.250g, 0.0012 mole) was added to a flask under argon and stirred in THFuntil dissolved. Lithium hexamethyldisilane (1.22 mL, 0.00122 mole) wasadded dropwise. The solution stirred for 30 minutes until it turned deepred. 3-Br-isothiocyanate (Compound 51a) (0.261 g, 0.00122 mole) wasadded and the reaction became deeper red. Acetic acid (0.076 mL, 0.00132mole) and hydrazine hydrate (0.059 mL, 0.00122 mole) were added. Thereaction was refluxed at 80° C. for 18 hours. Upon completion, 1 mL ofwater was added to the reaction. The solution was poured over a dryingcolumn and extracted from the column using dichloromethane. The solventwas blown off with nitrogen gas and the crude material dissolved in DMSOfor purification on reverse phase HPLC. The pure fractions werecollected and lyophilized to yield the title compound (Compound 568) asa pale yellow solid. MS m/z 401 (M+H)⁺;

[1420] HPLC: 100% pure (UV)

[1421]¹HNMR: 1.2(d, 3H), 3.7(q, 1H), 3.8(d, 6H), 7.0(m, 1H), 7.1(s, 1H),7.2(d, 2H), 7.25(s, 1H), 7.55(s, 1H), 8.8(s, 1H).

[1422] *S isomer has rotation: α(MeOH)=−62.60

[1423] The absolute configuration has not been determined.

EXAMPLE 53

[1424]*R-(3-Bromo-phenyl)-(6,7-dimethoxy-4-ethyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amineCompound 555 (Method A)

[1425] *R-5,6-Dimethoxy-3-ethyl-indan-1-one (Intermediate W(*R)) (0.250g, 0.0011 mole) was added to a flask under argon and stirred in THFuntil dissolved. Lithium hexamethyldisilane (1.2 mL, 0.0012 mole) wasadded dropwise. The solution stirred for 30 minutes until it turned deepred. 3-Br-isothiocyanate (Compound 51a) (0.257 g, 0.0012 mole) was addedand the reaction became deeper red. Acetic acid (0.069 mL, 0.00121 mole)and hydrazine hydrate (0.058 mL, 0.0012 mole) were added. The reactionwas refluxed at 80° C. for 18 hours. Upon completion, 1 mL of water wasadded to the reaction. The solution was poured over a drying column andextracted from the column using dichloromethane. The solvent was blownoff with nitrogen gas and the crude material dissolved in DMSO forpurification on reverse phase HPLC. The pure fractions were collectedand lyophilized to yield the title compound (Compound 555) as a paleyellow solid. MS m/z 415 (M+H)⁺;

[1426] HPLC: 100% pure (UV);

[1427]¹HNMR: 0.5(t, 3H), 1.7(m, 1H), 1.8(m, 1H), 3.7(t, 1H), 3.8(d, 6H),6.95(d, 1H), 7.1(d, 1H), 7.2(m, 3H), 7.3(s, 1H), 8.7(s, 1H).

[1428] *R isomer has rotation: α(MeOH)=+74.64

[1429] The absolute configuration has not been determined.

EXAMPLE 54

[1430]*S-(3-Bromo-phenyl)-(6,7-dimethoxy-4-ethyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine,Compound 570 (Method A)

[1431] *S-5,6-Dimethoxy-3-ethyl-indan-1-one (Intermediate W(*S)) (0.250g, 0.0011 mole) was added to a flask under argon and stirred in THFuntil dissolved. Lithium hexamethyldisilane (1.2 mL, 0.0012 mole) wasadded dropwise. The solution stirred for 30 minutes until it turned deepred. 3-Br-isothiocyanate (Compound 51a) (0.257 g, 0.0012 mole) was addedand the reaction became deeper red. Acetic acid (0.069 mL, 0.00121 mole)and hydrazine hydrate (0.058 mL, 0.0012 mole) were added. The reactionwas refluxed at 80° C. for 18 hours. Upon completion, 1 mL of water wasadded to the reaction. The solution was poured over a drying column andextracted from the column using dichloromethane. The solvent was blownoff with nitrogen gas and the crude material dissolved in DMSO forpurification on reverse phase HPLC. The pure fractions were collectedand lyophilized to yield the title compound (Compound 570) as a paleyellow solid. MS m/z 415 (M+H)⁺;

[1432] HPLC: 100% pure (UV);

[1433]¹HNMR: 0.5(t, 3H), 1.8(m, 2H), 3.7(t, 1H), 3.8(d, 6H), 6.95(d,1H), 7.1(d, 1H), 7.2(m, 3H), 7.3(s, 1H), 8.7(s, 1H).

[1434] *S isomer has rotation: α(MeOH)=−53.85

[1435] The absolute configuration has not been determined.

EXAMPLE 55

[1436]3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazole-1-carboxylicacid phenyl ester (Method O), Compound 433

[1437] To a mixture of(6,7-Dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine(Compound 14) (1.5 g g, 4.2 mmol), Phenyl chloroformate (Compound 55a)(0.76 mL, 6.3 mmole) and THF (10 mL) was added Diisopropylethylamine(DIPEA) (1.4 mL, 8.4 mmole) at room temperature with stirring. Thereaction was stirred at room temperature over night. The reaction wasquenched with saturated sodium bicarbonate and extracted with ethylacetate. The solvent was dried over sodium sulfate and removed viarotovap to give a crude material (Compound 433). MS m/z 446.1 (M+H)⁺.

EXAMPLE 56

[1438]3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazole-1-carboxylicacid (2-methylamino-ethyl)-amide, Compound 524 (Method P)

[1439]3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazole-1-carboxylicacid phenyl ester (Compound 433) (0.50 g, 1.12 mmol) andN-1-Methyl-ethane-1,2-diamine (Compound 56a) (0.12 mL, 1.3 mmol) weretaken up into 5 mL of DMSO. The reaction was stirred at room temperatureover night. The reaction was quenched with sat. sodium bicarbonate andextracted with ethyl acetate.

[1440] The solvent was dried over sodium sulfate and removed viarotovap. The crude material was prepared on the Gilson HPLC andlyophilization produced the title compound as a TFA salt. MS m/z 426.3(M+H)⁺;

[1441]¹HNMR (DMSO-d₆): 2.60 (s, 3H), 3.12 (m, 2H), 3.24 (s, 2H), 3.58(q, 2H), 3.78 (s, 3H), 3.81 (s, 3H), 6.55 (t, 1H), 7.21 (m, 2H), 7.32(d, 1H), 7.49 (d, 1H), 7.90 (s, 1H), 8.15 (t, 1H), 8.60 (s, 1H), 9.22(s, 1H).

EXAMPLE 57

[1442](3-Fluoro-phenyl)-(2H-8-oxa-2,3-diaza-cyclopenta[a]inden-1-yl)-amine,Compound 380 (Method A)

[1443] To a mixture of benzofuran-3-one (Compound 57a) (0.150 g, 0.00112mol), 3-fluoro-phenyl isothiocyanate (Compound 4a) (0.259 g, 0.00134mmol) and THF (2.00 mL) was added lithium hexamethyldisilane (1.34 mL,0.00134 mol) dropwise at room temperature with stirring. The reactionmixture was stirred for 12 h. Hydrazine (0.084 mL, 0.00268 mol) andacetic acid (0.154 mL, 0.00268 mol) was added to the reaction mixture,which was then heated at reflux temperature for 48 h. The reactionsolution was then diluted with ethyl acetate, washed with water anddried over MgSO₄. The solvent was removed in vacuo and the titlecompound was purified by HPLC with a C-18 reversed phase column andCH₃CN—H₂O-TFA as gradient solvents. The title compound was obtained as aTFA salt. MS m/z 268 (M+H)⁺;

[1444]¹HNMR (DMSO-d₆): 6.55(dt, 1H), 6.95(d, 1H), 7.05(d, 1H), 7.20(dd,1H), 7.40(m, 2H), 7.65(d, 1H), 7.75(d, 1H), 9.00(br s, 1H).

EXAMPLE 58

[1445] 2,2-Dimethyl-propionic acid3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-ylmethyl ester Compound 409 (Method L)

[1446] A mixture of(3-fluoro-phenyl)-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine(Compound 14) (1.25 g, 0.00385 mol) diisopropylethylamine (1.00 mL,0.00578 mol), chloromethylpivalate (0.833 mL, 0.00578 mol) and potassiumiodide (0.960 g, 0.00578 mol) in THF (19 mL) was heated to 75° C. for 12h. The mixture was diluted with ethyl acetate and washed with brine anddried over MgSO₄. The title compound which came out first was separatedby HPLC with C-18 reversed phase column and CH₃CN—H₂O-TFA as gradientsolvents. However, this isomer was contaminated with the startingmaterial(3-fluro-phenyl)-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine(Compound 14). The title compound was further purified by silica gelcolumn chromatography (pre-washed with 1% Et₃N in Hexanes) using 2:1Hexanes:ethyl acetate as the eluent. MS m/z 440.1 (M+H)⁺;

[1447]¹HNMR (DMSO-d₆): 1.20(s, 9H), 3.40(s, 2H), 3.90(s, 3H), 3.96(s,3H), 6.20(s, 2H), 6.57(m, 1H), 6.82(d, 1H), 6.95(m, 1H), 7.03(s, 1H),7.15(m, 1H), 7.27(s, 1H).

EXAMPLE 59

[1448] 2,2-Dimethyl-propionic acid3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-2-ylmethyl ester Compound 408 (Method L)

[1449] A mixture of(3-fluoro-phenyl)-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine(Compound 14) (1.25 g, 0.00385 mol) diisopropylethylamine (1.00 mL,0.00578 mol), chloromethylpivalate (0.833 mL, 0.00578 mol) and potassiumiodide (0.960 g, 0.00578 mol) in THF (19 mL) was heated to 75° C. for 12h. The mixture was diluted with ethyl acetate and washed with brine anddried over MgSO₄. The title compound which came out second was separatedby HPLC with C-1 8 reversed phase column and CH₃CN—H₂O-TFA as gradientsolvents. However, this isomer was contaminated with the startingmaterial(3-fluro-phenyl)-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine(Compound 14). The title compound was further purified by silica gelcolumn chromatography (pre-washed with 1% Et₃N in Hexanes) using 2:1Hexanes ethyl acetate as the eluent. MS m/z 440.1 (M+H)⁺;

[1450]¹HNMR (DMSO-d₆): 1.22(s, 9H), 3.40(s, 2H), 3.90(s, 3H), 3.93(s,3H), 5.94(s, 2H), 6.62(m, 2H), 6.72(d, 1H), 6.97(s, 1H), 7.21(m, 1H),7.33(s, 1H), 7.56(bs, 1H).

EXAMPLE 60

[1451] 5,6-Bis[3-tetrahydro-pyran-2-yloxy)-propoxy]-indan-1-one,Intermediate Y

[1452] A mixture of 5,6-dihydroxy-indan-1-one (Intermediate O) (2.00 g,0.0122 mole), potassium carbonate (4.22 g, 0.0305 mol),2-(3-chloro-propoxy)-tetrahydro-pyran (Compound 18a) (4.36 g, 0.0244mol) and potassium iodide (4.00 g, 0.0244 mol) in DMF (20 mL) wasstirred at 60° C. for 36 h. The reaction mixture was then diluted withethyl acetate, washed with water and dried over MgSO₄. The solvent wasremoved in vacuo and the title compound was purified by silica gelcolumn chromatography using 3:1 Hexanes:ethyl acetate as the eluent. MSm/z 449 (M+H)⁺;

[1453]¹HNMR (CDCl₃): 1.60(m, 12H), 2.13(m, 4H), 2.70(t, 2H), 3.12(t,3H), 3.52(m, 4H), 3.90(m, 2H), 4.20(m, 4H), 4.60(s, 2H), 6.90(s, 1H),7.18(s, 1H).

EXAMPLE 61

[1454]3-[3-(3-Fluoro-phenylamino)-6-(3-hydroxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol,Compound 398 (Method A)

[1455] To a mixture of5,6-bis[3-tetrahydro-pyran-2-yloxy)-propoxy]-indan-1 one (IntermediateY) (0.100 g, 0.00022 mol) 3-fluorophenyl isothiocyanate (Compound 4a)(0.031 mL, 0.00026 mol) and THF (4 mL) was added lithiumhexamethyldisilane (0.260 mL, 0.00026 mol) dropwise at room temperaturewith stirring. The reaction mixture was stirred for 12 h. Hydrazine(0.008 mL, 0.00026 mol) and acetic acid (0.015 mL, 0.00026 mol) wasadded to the reaction mixture, which was then heated at refluxtemperature for 24 h. The reaction solution was then diluted with ethylacetate, washed with water and dried over MgSO₄. The solvent was removedin vacuo and the title compound was purified by HPLC with a C-18reversed phase column and CH₃CN—H₂O-TFA as gradient solvents. The titlecompound was obtained as a solid TFA salt. MS m/z 414.3 (M+H)⁺;

[1456]¹HNMR (MeOH-d₄): 2.05(m, 4H), 3.50(s, 2H), 3.83(m, 4H), 4.20(t,4H), 6.76(m, 1H), 6.95(m, 2H), 7.26(s,1H), 7.28(s,1H), 7.36(m,1H).

EXAMPLE 62

[1457] 5-Ethoxy-6-[3-(tetrahydro-pyran-2-yloxy)-propoxy-indan-1-one,Intermediate Z

[1458] A mixture of 5,6-dihydroxy-indan-1-one (Intermediate O) (2.00 g,0.0122 mole), potassium carbonate (4.22 g, 0.0305 mol) and ethyl bromide(0.911 mL, 0.0122 mol) in DMF (20 mL) was stirred at room temperaturefor 12 h. The reaction mixture was then diluted with ethyl acetate,washed with water and dried over MgSO₄. The solvent was removed invacuo. The resulting 5-ethoxy-6-hydroxy-indan-1-one (Compound 62a) waspurified by silica gel column chromatography using 3:1 Hexanes:ethylacetate as the eluent.

[1459] The mixture of 5-ethoxy-6-hydroxy-indan-1-one (Compound 62a)(0.520 g, 0.00271 mol), 2-(3-chloro-propoxy)-tetrahydro-pyran (Compound18a) (0.938 g, 0.00542 mol), potassium carbonate (0.936 g, 0.00678 mol)and potassium iodide (0.900 g, 0.00542 mol) in DMF (5.5 mL) was stirredat 60° C. for 12 h. The reaction mixture was then diluted with ethylacetate, washed with water and dried over MgSO₄. The solvent was removedin vacuo and the title compound was purified by silica gel columnchromatography using 3:1 Hexanes:ethyl acetate as the eluent. MS m/z334.2 (M+H)⁺;

[1460]¹HNMR (CDCl₃): 1.60(m, 9H), 2.18(m, 2H), 2.65(t, 2H), 3.06(t, 2H),3.38(m, 2H), 3.85(m, 2H), 4.18(m, 4H), 4.62(t, 1H), 6.84(s, 1H), 7.22(s,1H).

EXAMPLE 63

[1461]3-[6-Ethoxy-3-(3-fluoro-phenylamino)-2,4-dihydro-indeno]1,2-c]pyrazol-7-yloxy]-propan-1-ol,Compound 365 (Method A)

[1462] To a mixture of5-Ethoxy-6-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-indan-1-one(Intermediate Z) (0.100 g, 0.0003 mol), 3-fluorophenyl isothiocyanate(Compound 4a) (0.043 mL, 0.00036 mol) and THF (3 mL) was added lithiumhexamethyldisilane (0.360 mL, 0.00036 mol) dropwise at room temperaturewith stirring. The reaction mixture was stirred for 5 h. Hydrazine(0.011 mL, 0.00036 mol) and acetic acid (0.021 mL, 0.00036 mol) wasadded to the reaction mixture, which was then heated at refluxtemperature for 12 h. The reaction solution was then diluted with ethylacetate, washed with water and dried over MgSO₄. The solvent was removedin vacuo and the crude material was purified on the reverse phase HPLCand converted to the desired product upon standing in the 0.1% TFAsolution. Lyophilization yielded the title compound as a white powder.MS m/z 384.4 (M+H)⁺;

[1463]¹HNMR (CDCl₃): 1.47(t, 3H), 2.12(m, 2H), 3.43(s, 2H), 3.90(t, 2H),4.08(q, 2H), 4.22(t, 2H), 4.85(bs, 1H), 6.89(m, 2H), 6.97(s, 1H),7.18(s, 1H), 7.32(m, 2H), 9.42(bs, 1H).

EXAMPLE 64

[1464] 6-Ethoxy-5-f3-(tetrahydro-pyran-2-yloxy)-propoxy]-indan-1-one,Intermediate AA

[1465] A mixture of 5,6-dihydroxy-indan-1-one (Intermediate O) (1.80 g,0.01098 mole), potassium carbonate (3.80 g, 0.02744 mol),2-(3-chloro-propoxy)-tetrahydro-pyran (Compound 18a) (1.37 g, 0.00769mol) and potassium iodide (1.28 g, 0.00769 mol) in DMF (20 mL) wasstirred at 60° C. for 4 hours. To this mixture was then added ethylbromide (1.64 mL, 0.02196 mol) and continued to heat for further 4 h.The reaction mixture was then diluted with ethyl acetate, washed withwater and dried over MgSO₄. The solvent was removed in vacuo and thetitle compound was purified by silica gel column chromatography using3:1 Hexanes:ethyl acetate as the eluent. MS m/z 334.2 (M+H)⁺;

[1466]¹HNMR (CDCl₃): 1.65(m, 9H), 2.20(m, 2H), 2.68(t, 2H), 3.15(t, 2H),3.55(m, 2H), 4.10(m, 6H), 4.60(m, 1H), 6.92(s, 1H), 7.16(s, 1H).

EXAMPLE 65

[1467]3-[7-Ethoxy-3-(3-fluoro-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol,Compound 382 (Method A)

[1468] To a mixture of6-Ethoxy-5-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-indan-1-one(Intermediate AA) (0.100 g, 0.0003 mol), 3-fluorophenyl isothiocyanate(Compound 4a) (0.043 mL, 0.00036 mol) and THF (3 mL) was added lithiumhexamethyldisilane (0.360 mL, 0.00036 mol) dropwise at room temperaturewith stirring. The reaction mixture was stirred for 48 h. Hydrazine(0.011 mL, 0.00036 mol) and acetic acid (0.021 mL, 0.00036 mol) wasadded to the reaction mixture, which was then heated at refluxtemperature for 12 h. The reaction solution was then diluted with ethylacetate, washed with water and dried over MgSO₄. The solvent was removedin vacuo and the crude material was purified on the reverse phase HPLCand converted to the desired product upon standing in the 0.1% TFAsolution. Lyophilization yielded the title compound as a white powder.MS m/z 384.2 (M+H)⁺;

[1469]¹HNMR (DMSO-d₆): 1.28(t, 3H), 2.90(m, 2H), 3.42(s, 2H), 3.60(t,2H), 4.12(m, 4H), 6.54(m, 1H), 6.88(d, 1H), 7.20(m, 4H), 8.80(bs, 1H).

EXAMPLE 66

[1470] 3-thiophene-2-yl-acrylic acid, Intermediate AB

[1471] A mixture of thiophene-2-carbaldehyde (Compound 66a) (1.20 g,0.0107 mol), malonic acid (1.11 g, 0.0107 mol) and ammonium acetate(0.825 g, 0.0107 mol) in DMF (8.5 mL) was heated to 100° C. for 3 h. Thesystem was diluted with ethyl acetate and washed with water and driedover MgSO₄. The solvent was removed in vacuo and the title compound waspurified by silica gel column chromatography using 3:1 Hexanes:ethylacetate as the eluent.

[1472]¹HNMR (CDCl3): 6.25(d, 1H), 7.08(m, 1H), 7.30(d, 1H), 7.42(d, 1H),7.88(d, 1H).

EXAMPLE 67

[1473] 3-thiophene-2-yl-propionic acid, Intermediate AC

[1474] A mixture of 3-thiophene-2-yl-acrylic acid (Intermediate AB)(2.00 g, 0.01299 mol), 10% Pd on C (2.00 g) in methanol (200 mL) wasstirred under the atmosphere of H₂ (50 PSI) for 18 h. The resultingsystem was purged with N₂ and then filtered through a pad of celite.Organics were dried over MgSO₄ and the solvent was removed in vacuo toprovide 3-thiophene-2-yl-propionic acid. ¹HNMR (CDCl3): 2.76(t, 2H),3.20(t, 2H), 6.82(d, 1H), 6.95(m, 1H), 7.15(d, 1H)

EXAMPLE 68

[1475] 5,6-dihydro-cyclopenta[b]thiophen-4-one, Intermediate AD

[1476] To a solution of 3-thiophene-2-yl-propionic acid (IntermediateAC) (1.75 g, 0.01122 mol) in dichloromethane (50 mL) was added SOCl₂(1.67 mL, 0.02244 mol) and stirred at room temperature for 6 h. Thissolution was added dropwise to a suspension of AlCl₃ (2.98 g, 0.02244mol) in dichloromethane (50 mL) over 45 minutes. The resulting mixturewas stirred at room temperature for 12 h. The system was quenched bydropwise addition of water (10 mL) and extracted with dichloromethane.The organics were dried with MgSO₄ and the solvent was removed in vacuo.The title compound was purified by silica gel column chromatographyusing 4:1 Hexanes:ethyl acetate as the eluent. MS m/z 139.1 (M+H)⁺;

[1477]¹HNMR (CDCl₃): 3.01(t, 2H), 3.18(t, 2H), 7.15(d, 1H), 7.32(d, 1H).

EXAMPLE 69

[1478](5,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(3-ethoxy-phenyl)-amine,Compound 405 (Method A)

[1479] To a mixture of 5,6-dihydro-cyclopenta[b]thiophen-4-one(Intermediate AD) (0.065 g, 0.00047 mol) 3-ethoxy-phenyl isothiocyanate(Compound 69a) (0.108 g, 0.00056 mol) and THF (2.5 mL) was added lithiumhexamethyldisilane (0.560 mL, 0.00056 mol) dropwise at room temperaturewith stirring. The reaction mixture was stirred for 3 h. Hydazine (0.036mL, 0.00112 mol) and acetic acid (0.0032 mL, 0.00056 mol) was added tothe reaction mixture, which was then heated to 50° C. for 8 h. Thereaction solution was then diluted with ethyl acetate, washed with waterand dried over MgSO₄. The solvent was removed in vacuo and the titlecompound was purified by HPLC with a C-18 reversed phase column andCH₃CN—H₂O-TFA as gradient solvents. The title compound was obtained as asolid TFA salt. MS m/z 298.2 (M+H)⁺;

[1480]¹HNMR (DMSO-d₆): 1.25(t, 1H), 3.52(s, 2H), 3.88(q, 2H), 5.80(bs,1H), 6.28(m, 1H), 6.65(m, 2H), 7.05(t, 1H), 7.18(d, 1H), 7.58(d, 1H),8.60(bs, 1H).

EXAMPLE 70

[1481]3-6-Ethoxy-3-(3-ethoxy-phenylamino)-2,4-dihydro-indeno{1,2-c}pyrazol-7-yloxyl-propan-1-ol,Compound 388 (Method A)

[1482] To a mixture of5-Ethoxy-6-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-indan-1-one(Intermediate Z) (0.100 g, 0.0003 mol), 3-ethoxyphenyl isothiocyanate(Compound 69a) (0.043 mL, 0.00036 mol) and THF (3 mL) was added lithiumhexamethyldisilane (0.360 mL, 0.00036 mol) dropwise at room temperaturewith stirring. The reaction mixture was stirred for 5 h. Hydrazine(0.011 mL, 0.00036 mol) and acetic acid (0.021 mL, 0.00036 mol) wasadded to the reaction mixture, which was then heated at refluxtemperature for 12 h. The reaction solution was then diluted with ethylacetate, washed with water and dried over MgSO₄. The solvent was removedin vacuo and the crude material was purified on the reverse phase HPLCand converted to the desired product upon standing in the 0.1% TFAsolution. Lyophilization yielded the title compound as a white powder.MS m/z 410.2 (M+H)⁺;

[1483]¹HNMR (DMSO-d₆): 8.65(bs, 1H), 7.14(m, 3H), 6.79(s, 1H), 6.71(d,1H), 6.37(d, 1H), 4.03(m, 6H), 3.60(t, 2H), 3.40(s, 1H), 1.88(m, 2H),1.30(m, 6H).

[1484] Biological Activity

[1485] Biological Activities of the Compounds of the Invention

[1486] Compounds within the scope of this invention were subjected tovarious biological tests. Results of these tests showed that compoundswithin the scope of this invention inhibited PDGF-R kinase activity.Compounds within the scope of this invention also exhibited inhibitoryactivity against c-Abl kinase. In addition, compounds within the scopeof this invention inhibited cell (including normal tissue cells, tumorcells and leukemia cells) proliferation in the presence or absence ofPDGF stimulation. Other studies demonstrated that compounds within thescope of this invention inhibited angiogenesis and compounds were shownto have anti-tumor activity. Further, compounds within the scope of thisinvention sensitized tumor cells for radiation treatment. Pro-drugs ofcompounds within the scope of the invention were demonstrated to convertback to parent compounds in vivo.

[1487] The following representative assays were performed in determiningthe biological activities of compounds within the scope of theinvention. They are given to illustrate the invention in a non-limitingfashion.

[1488] 1. Inhibition of PDGF-Receptor Kinase Activity

[1489] PDGF-R kinase activity was assayed by its ability tophosphorylate one of its target proteins, PLCγ, in a cell-free system,in particular, a PLC1 peptide comprising the tyrosine residue where thephosphorylation occurs was used for the assay.

[1490] Materials

[1491] The following reagents were prepared for the assay:

[1492] 10× Kinase Buffer (500 mM Tris-HCl pH=8, 100 mM MgCl₂, 1 mMNa₃VO₄); 10 mM DTT (final concentration at 1 mM in assay); 10 mM ATP(final concentration at 5 μM in assay); ³³P-γ-ATP (Cat. No.: NEG/602H.2000-3000 Ci/mmol) purchased from NEN; Purified, soluble, recombinantPDGF-receptor beta enzyme comprising the tyrosine kinase domain (fromamino acid 545 to 1106 of GenBank Access NO: AAA36427 ) at 0.4 mg/mL;Enzyme Dilution Buffer (50 mM Tris-HCl pH=8.0, 0.1% BSA); Wash/StopBuffer (PBS +100 mM EDTA); NEN Streptavidin Flashplates (Cat. No.:SMP-103) which binds to the biotinylated PLC1 peptide but not the PDGF-Renzyme; PLC1 peptide (Biotin-KHKKLAEGSAYEEV-Amide) at 1 mM in 50 mMTris-HCL with pH of 8.0.

[1493] Procedure

[1494] Reagents were first mixed according the following regimen: ONEPLATE (μl) PER WELL (μl) 10X Kinase Buffer 1100 10 10 mM DTT 1100 10 10mM cold ATP 5.5 0.05 1 mM PLC1 Peptide 2.75 0.025 ³³P-γ-ATP (10 μCi/μl)8.8 0.08 H₂O 5475 49.77

[1495] The above reaction mixture was dispensed into each well of aFlashplate at 70 μl/well. To test the effect of a compound on PDGF-Rkinase activity, the test compound either in a fixed concentration or inserially diluted concentrations in 100% DMSO was added to appropriatewells at 1 μl/well.

[1496] Enzyme PDGF-R was diluted in Enzyme dilution buffer as following:Enzyme Dilution Buffer 3289 μl PDGF-R enzyme  100 μl

[1497] The kinase reaction was initiated by adding 30 μl of dilutedPDGF-R enzyme solution to each well on the Flashplate containing hot ATPand PLC1, except wells of column 12 rows E through H, which were used tocalculate the plate background. The Flashplate was swirled to mix andwas incubated at 30° C. for 60 minutes. Then, the reaction mixture wasdiscarded and the Flashplate was washed 3 times each with 200 μlWash/Stop Buffer. Subsequently, each well on the Flashplate was filledwith 200 μl of Wash/Stop buffer. The amount of ³³P retained in each wellwas measured using a Packard TopCount after the plate was sealed with atransparent plate sealer.

[1498] When a test compound inhibited the PDGF-R kinase activity, thewell containing such a compound contained less ³³P as compared to thewell without the compound. The percentage of inhibition of the testcompound on PDGF-R kinase activity is defined as the amount of ³³Pretained in the well containing the compound divided by the amount of³³P in the well without the compound. Tested under the described assayconditions, more than 600 compounds within the scope of the invention ata final concentration of 10 μM have demonstrated inhibitory effect onPDGF-R kinase activity.

[1499] In order to test the potency of inhibition of present compounds,an IC₅₀ for an individual compound was measured using the aboveprocedure. As used herein, the IC₅₀ for PDGF-R kinase activity refers tothe concentration of an inhibitor at which the activity of the PDGF-Rkinase is reduced by one-half as compared with reactions containing noinhibitor.

[1500] Inhibition of PDGF-R kinase activity preferably refers to an IC₅₀of less than or equal to about 75 μM using the assay described above.Preferably, the compound can inhibit PDGF-R kinase activity with an IC₅₀of less than or equal to about 10 μM, more preferably less than or equalto about 1 μM, most preferably less than or equal to about 0.1 μM. LowerIC₅₀ values are preferred because the IC₅₀ provides an indication as tothe effectiveness of the compound. Other factors known in art, such ascompound half-life, bio-distribution, and toxicity should also beconsidered for therapeutic uses. Such factors may enable a compound witha higher IC₅₀ to have greater in vivo efficacy than a compound having alower IC₅₀.

[1501] Representative compounds of the present invention were tested forPDGF-R kinase activity with % inhibition and / or IC₅₀ results as listedin Table A. TABLE A IC50 and percent of inhibition of compounds onPDGF-R kinase activity Percent Inhibition CPD NAME @10 uM IC50 (μM) 1(2,4-Dihydro-indeno[1,2-c]pyrazol-3-yl)-phenyl- 91 0.317 amine 2(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 91 0.006yl)-phenyl-amine 3 (4-Chloro-phenyl)-(2,4-dihydro-indeno[1,2-c]pyrazol-90 0.157 3-yl)-amine 4 (3-Chloro-phenyl)-(6,7-dimethoxy-2,4-dihydro- 900.003 indeno[1,2-c]pyrazol-3-yl)-amine 5(4-Chloro-phenyl)-(6,7-dimethoxy-2,4-dihydro- 91 0.659indeno[1,2-c]pyrazol-3-yl)-amine 6(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 75 0.131yl)-(4-methoxy-phenyl)-amine 7(6-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 92 0.217 phenyl-amine8 (5-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl- 98 0.054phenyl-amine 9 (2-Chloro-phenyl)-(6,7-dimethoxy-2,4-dihydro- 89 0.11indeno[1,2-c]pyrazol-3-yl)-amine 104-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol- 68 2.073-ylamino)-benzoic acid ethyl ester 113-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol- 97 0.01573-ylamino)-benzoic acid methyl ester 12(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 76 0.056yl)-(2-fluoro-phenyl)-amine 13(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 91 0.0065yl)-(4-fluoro-phenyl)-amine 14(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 108 0.0017yl)-(3-fluoro-phenyl)-amine 15(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 79 1.92yl)-(2-trifluoromethoxy-phenyl)-amine 16(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 79 4yl)-(4-trifluoromethoxy-phenyl)-amine 17(2,4-Dichloro-phenyl)-(6,7-dimethoxy-2,4-dihydro- 79 354indeno[1,2-c]pyrazol-3-yl)-amine 18(3,4-Dichloro-phenyl)-(6,7-dimethoxy-2,4-dihydro- 65 0.23indeno[1,2-c]pyrazol-3-yl)-amine 19(3,5-Dichloro-phenyl)-(6,7-dimethoxy-2,4-dihydro- 91 0.174indeno[1,2-c]pyrazol-3-yl)-amine 20(2,3-Dichloro-phenyl)-(6,7-dimethoxy-2,4-dihydro- 77 1.095indeno[1,2-c]pyrazol-3-yl)-amine 21(6-Chloro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 103 0.121 phenyl-amine22 (7-Methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 96 0.045phenyl-amine 23 (5-Methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 871.94 phenyl-amine 24 (6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-71 0.084 phenyl-amine 25(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 62 4.766yl)-(4-trifluoromethyl-phenyl)-amine 26(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 92 0.037yl)-(3-trifluoromethyl-phenyl)-amine 27(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 71 0.655yl)-(2-methoxy-phenyl)-amine 28(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 96 19.14yl)-(2-trifluoromethyl-phenyl)-amine 29(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 99 0.01yl)-(3-methoxy-phenyl)-amine 30(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 107 0.016yl)-pyridin-3-yl-amine 31(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 59 0.115yl)-o-tolyl-amine 32 (6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-79 0.012 yl)-m-tolyl-amine 33(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 59 1.415yl)-p-tolyl-amine 34 (2,5-Dichloro-phenyl)-(6,7-dimethoxy-2,4-dihydro-57 6.987 indeno[1,2-c]pyrazol-3-yl)-amine 353-Phenylamino-2H-indeno[1,2-c]pyrazol-4-one 88 2.063 36[3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol- 85 0.0333-ylamino)-phenyl]-methanol 37(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 80 1.978yl)-(1H-indazol-6-yl)-amine 383-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol- 74 0.0313-ylamino)-phenol 39 (7-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-92 0.018 phenyl-amine 40N-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol- 63 5.953-yl)-N′,N″-dimethyl-benzene-1,2-diamine 41(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 83 0.0336yl)-(3,5-dimethoxy-phenyl)-amine 42(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 85 0.692yl)-(3,4,5-trimethoxy-phenyl)-amine 43(2-Bromo-phenyl)-(6,7-dimethoxy-2,4-dihydro- 60 0.195indeno[1,2-c]pyrazol-3-yl)-amine 44(3-Bromo-phenyl)-(6,7-dimethoxy-2,4-dihydro- 94 0.00054indeno[1,2-c]pyrazol-3-yl)-amine 45(4-Bromo-phenyl)-(6,7-dimethoxy-2,4-dihydro- 86 2.164indeno[1,2-c]pyrazol-3-yl)-amine 46(5-Chloro-2-methyl-phenyl)-(6,7-dimethoxy-2,4- 51 14.15dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 47(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 47 NTyl)-(2,4-dimethoxy-phenyl)-amine 48(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 39 NTyl)-(2,5-dimethoxy-phenyl)-amine 49(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 72 3.066yl)-(3,4-dimethoxy-phenyl)-amine 503-Phenylamino-2,4-dihydro-indeno[1,2-c]pyrazol-4- 38 11.37 ol 51(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 30 26.75yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine 52(4,5-Dihydro-2H-6-thia-1,2-diaza-as-indacen-3-yl)- 71 2.4 phenyl-amine53 (3-Chloro-4-fluoro-phenyl)-(6,7-dimethoxy-2,4- 94 0.05859dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 54(3-Benzyloxy-phenyl)-(6,7-dimethoxy-2,4-dihydro- 76 0.0348indeno[1,2-c]pyrazol-3-yl)-amine 55(2,5-Difluoro-phenyl)-(6,7-dimethoxy-2,4-dihydro- 76 0.636indeno[1,2-c]pyrazol-3-yl)-amine 56(5-Chloro-2-methoxy-phenyl)-(6,7-dimethoxy-2,4- 36 8.402dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 57(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 71 2.151yl)-(2-isopropyl-phenyl)-amine 58(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 40 8.524yl)-(2-ethyl-phenyl)-amine 594-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol- 71 1.8183-ylamino)-benzonitrile 613-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol- 71 0.1373-ylamino)-benzonitrile 62Benzo[1,3]dioxol-5-yl-(6,7-dimethoxy-2,4-dihydro- 85 0.313indeno[1,2-c]pyrazol-3-yl)-amine 63Benzyl-(6,7-dimethoxy-2,4-dihydro-indeno[1,2- 94 0.1909c]pyrazol-3-yl)-amine 64[6-(4-Methyl-piperazin-1-yl)-2,4-dihydro-indeno[1,2- 118 0.449c]pyrazol-3-yl]-phenyl-amine 65Phenyl-(6-piperidin-1-yl-2,4-dihydro-indeno[1,2- 76 1.535c]pyrazol-3-yl)-amine 66N3-Phenyl-2,4-dihydro-indeno[1,2-c]pyrazole-3,6- 108 0.092 diamine 67Cyclohexyl-(6,7-dimethoxy-2,4-dihydro-indeno[1,2- 77 0.617c]pyrazol-3-yl)-amine 69(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 18yl)-(2-morpholin-4-yl-ethyl)-amine 70(3,5-Bis-trifluoromethyl-phenyl)-(6,7-dimethoxy-2,4- 41.5 16.85dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 71[5-(3-Dimethylamino-propoxy)-2,4-dihydro- 110 0.185indeno[1,2-c]pyrazol-3-yl]-phenyl-amine 72(3-Chloro-phenyl)-[5-(3-dimethylamino-propoxy)-2,4- 96 0.283dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 73[5-(3-Dimethylamino-propoxy)-2,4-dihydro- ˜30 >>50indeno[1,2-c]pyrazol-3-yl]-(4-fluoro-phenyl)-amine 74[5-(3-Dimethylamino-propoxy)-2,4-dihydro- 102 0.424indeno[1,2-c]pyrazol-3-yl]-(3-methoxy-phenyl)-amine 75[5-(3-Dimethylamino-propoxy)-2,4-dihydro- 115 0.575indeno[1,2-c]pyrazol-3-yl]-pyridin-3-yl-amine 76(4-Bromo-2-trifluoromethyl-phenyl)-(6,7-dimethoxy- 16 >>502,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 773-[5-(3-Dimethylamino-propoxy)-2,4-dihydro- 108 0.217indeno[1,2-c]pyrazol-3-ylamino]-benzoic acid methyl ester 78(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 85 1.291yl)-furan-2-yl-amine 79(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 56 3.705yl)-indan-5-yl-amine 81(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 29 85.95yl)-(2-piperidin-1-yl-ethyl)-amine 82(4-Fluoro-phenyl)-(6-methoxy-2,4-dihydro- 79 0.273indeno[1,2-c]pyrazol-3-yl)-amine 83(3-Bromo-phenyl)-(6-methoxy-2,4-dihydro- 93 0.0719indeno[1,2-c]pyrazol-3-yl)-amine 84(6-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 86 0.71pyridin-3-yl-amine 85 (2,5-Dimethoxy-phenyl)-(6-methoxy-2,4-dihydro- 615.823 indeno[1,2-c]pyrazol-3-yl)-amine 86(3,4-Dimethoxy-phenyl)-(6-methoxy-2,4-dihydro- 57 2.532indeno[1,2-c]pyrazol-3-yl)-amine 87(2,5-Difluoro-phenyl)-(6-methoxy-2,4-dihydro- 91 0.069indeno[1,2-c]pyrazol-3-yl)-amine 88(6-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 42 20.8(4-trifluoromethoxy-phenyl)-amine 89(6-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 88 0.886(4-trifluoromethyl-phenyl)-amine 90[5-(3-Dimethylamino-propoxy)-2,4-dihydro- 97 0.0087indeno[1,2-c]pyrazol-3-yl]-(3-fluoro-phenyl)-amine 91(3-Bromo-phenyl)-(6,7-dimethoxy-1-methyl-1,4- 76 2.969dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 92N6,N6-Dimethyl-N3-phenyl-2,4-dihydro-indeno[1,2- 75 0.383c]pyrazole-3,6-diamine 93(4,5-Dihydro-2H-benzo[g]indazol-3-yl)-phenyl-amine 88 1.027 94(5,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen- 95 0.4156-yl)-phenyl-amine 95 (3-Bromo-phenyl)-(2,9-dihydro-5,7-dioxa-2,3-diaza-91.0 0.063 cyclopenta[a]-s-indacen-1-yl)-amine 96(2,9-Dihydro-5,7-dioxa-2,3-diaza-cyclopenta[a]-s- 93.0 0.076indacen-1-yl)-(3-fluoro-phenyl)-amine 97(2,9-Dihydro-5,7-dioxa-2,3-diaza-cyclopenta[a]-s- 91.0 0.054indacen-1-yl)-(3-methoxy-phenyl)-amine 98(4-Fluoro-phenyl)-(5-methyl-2,4-dihydro-indeno[1,2- 26 30.69c]pyrazol-3-yl)-amine 99(3-Fluoro-phenyl)-(5-methyl-2,4-dihydro-indeno[1,2- 87.5 1.468c]pyrazol-3-yl)-amine 100(5-Methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 81 1.723pyridin-3-yl-amine 101 (2,5-Dimethoxy-phenyl)-(5-methyl-2,4-dihydro- 521.092 indeno[1,2-c]pyrazol-3-yl)-amine 102(2,4-Dimethoxy-phenyl)-(5-methyl-2,4-dihydro- 50 3.404indeno[1,2-c]pyrazol-3-yl)-amine 103(2,5-Difluoro-phenyl)-(5-methyl-2,4-dihydro- 43 4.099indeno[1,2-c]pyrazol-3-yl)-amine 104(5-Methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4- 36 0.666trifluoromethoxy-phenyl)-amine 105(5-Methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4- 69 1.884trifluoromethyl-phenyl)-amine 106(4-Fluoro-phenyl)-(4-methyl-2,4-dihydro-indeno[1,2- 38 1.048c]pyrazol-3-yl)-amine 107 (4-Methoxy-phenyl)-(4-methyl-2,4-dihydro- 561.275 indeno[1,2-c]pyrazol-3-yl)-amine 108(3-Fluoro-phenyl)-(4-methyl-2,4-dihydro-indeno[1,2- 82 0.3c]pyrazol-3-yl)-amine 109(4-Methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 83 0.537pyridin-3-yl-amine 110 (2,5-Dimethoxy-phenyl)-(4-methyl-2,4-dihydro- 800.189 indeno[1,2-c]pyrazol-3-yl)-amine 111(2,4-Dimethoxy-phenyl)-(4-methyl-2,4-dihydro- 95 0.11indeno[1,2-c]pyrazol-3-yl)-amine 112(2,5-Difluoro-phenyl)-(4-methyl-2,4-dihydro- 72 0.083indeno[1,2-c]pyrazol-3-yl)-amine 113(4-Methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4- 60 2.45trifluoromethoxy-phenyl)-amine 114(4-Methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3- 80 1.37trifluoromethyl-phenyl)-amine 1153-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol- 82 3.0563-ylamino)-benzoic acid 1163-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol- 96 0.00533-ylamino)-benzamide 117 N3-(3-Bromo-phenyl)-2,4-dihydro-indeno[1,2- 980.13 c]pyrazole-3,6-diamine 118N3-(3-Methoxy-phenyl)-2,4-dihydro-indeno[1,2- 74 0.0213c]pyrazole-3,6-diamine 119 N3-(3-Chloro-phenyl)-2,4-dihydro-indeno[1,2-90 0.0198 c]pyrazole-3,6-diamine 1203-(6-Amino-2,4-dihydro-indeno[1,2-c]pyrazol-3- 87 0.308 ylamino)-benzoicacid methyl ester 121 N3-(3-Fluoro-phenyl)-2,4-dihydro-indeno[1,2- 920.143 c]pyrazole-3,6-diamine 122(3-Bromo-phenyl)-[6-(4-methyl-piperazin-1-yl)-2,4- 70 0.0162dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 123(3-Methoxy-phenyl)-[6-(4-methyl-piperazin-1-yl)-2,4- 87 0.228dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 124(3-Chloro-phenyl)-[6-(4-methyl-piperazin-1-yl)-2,4- 94 0.0163dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 1253-(3-Bromo-phenylamino)-2,4-dihydro-indeno[1,2- 71 3.44c]pyrazole-6,7-diol 126(2,9-Dihydro-5,7-dioxa-2,3-diaza-cyclopenta[a]-s- 65 0.1758indacen-1-yl)-pyridin-3-yl-amine 1273-(2,9-Dihydro-5,7-dioxa-2,3-diaza-cyclopenta[a]-s- 89 0.421indacen-1-ylamino)-benzoic acid methyl ester 128(3-Chloro-phenyl)-(2,9-dihydro-5,7-dioxa-2,3-diaza- 88 0.05958cyclopenta[a]-s-indacen-1-yl)-amine 129[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-2,4- 53.5 0.0367dihydro-indeno[1,2-c]pyrazol-3-yl]-pyridin-3-yl-amine 130(3-Bromo-phenyl)-[7-methoxy-6-(3-morpholin-4-yl- 94.5 0.002148propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]- amine 131[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-2,4- 97 0.01297dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-methoxy- phenyl)-amine 132(3-Chloro-phenyl)-[7-methoxy-6-(3-morpholin-4-yl- 79 0.00537propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]- amine 1333-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-2,4- 53 0.03789dihydro-indeno[1,2-c]pyrazol-3-ylamino]-benzoic acid methyl ester 134(3-Fluoro-phenyl)-[7-methoxy-6-(3-morpholin-4-yl- 96 0.01006propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]- amine 135(3-Chloro-phenyl)-[6-(3-methoxy-propoxy)-2,4- 87 0.202dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 136(4-Fluoro-phenyl)-[6-(3-methoxy-propoxy)-2,4- 64.5 1.331dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 1373-[6-(3-Methoxy-propoxy)-2,4-dihydro-indeno[1,2- 71 2.11c]pyrazol-3-ylamino]-benzoic acid methyl ester 138(3-Fluoro-phenyl)-[6-(3-methoxy-propoxy)-2,4- 79.5 0.3011dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 139(3-Methoxy-phenyl)-[6-(3-methoxy-propoxy)-2,4- 80 0.09822dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 140[6-(3-Methoxy-propoxy)-2,4-dihydro-indeno[1,2- 56.5 0.01366c]pyrazol-3-yl]-phenyl-amine 141(3-Bromo-phenyl)-[6-(3-methoxy-propoxy)-2,4- 83.5 0.3192dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 142[6-(3-Methoxy-propoxy)-2,4-dihydro-indeno[1,2- 82.5 0.4534c]pyrazol-3-yl]-pyridin-3-yl-amine 143(4-Methoxy-phenyl)-[6-(3-methoxy-propoxy)-2,4- 67 8.124dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 144(4-Fluoro-phenyl)-(5-methoxy-2,4-dihydro- 96.5 0.8359indeno[1,2-c]pyrazol-3-yl)-amine 145(5-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 48.5 13.93(4-methoxy-phenyl)-amine 146(5-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 78.5 0.1603pyridin-3-yl-amine 147 (2,5-Dimethoxy-phenyl)-(5-methoxy-2,4-dihydro- 322.984 indeno[1,2-c]pyrazol-3-yl)-amine 148(2,4-Dimethoxy-phenyl)-(5-methoxy-2,4-dihydro- 57 8.601indeno[1,2-c]pyrazol-3-yl)-amine 149(5-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 27.5 8.37(3-trifluoromethoxy-phenyl)-amine 150(5-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 85 0.8226(3-trifluoromethyl-phenyl)-amine 151(6-Bromo-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3- 79 0.09184fluoro-phenyl)-amine 152(6-Bromo-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 80 0.1739pyridin-3-yl-amine 153 (6-Bromo-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-79 1.033 (2,5-difluoro-phenyl)-amine 154(6-Bromo-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3- 29 41.62trifluoromethoxy-phenyl)-amine 155(6-Bromo-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3- 53 8.11trifluoromethyl-phenyl)-amine 156(3-Methoxy-phenyl)-[7-methoxy-6-(3-pyrrolidin-1-yl- 87.5 0.001propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]- amine 1573-[7-Methoxy-6-(3-pyrrolidin-1-yl-propoxy)-2,4- 85 0.007dihydro-indeno[1,2-c]pyrazol-3-ylamino]-benzoic acid methyl ester 158(6-Bromo-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 87.5 0.1859phenyl-amine 159 [6-(3-Dimethylamino-propoxy)-2,4-dihydro- 92.5 0.09887indeno[1,2-c]pyrazol-3-yl]-(4-fluoro-phenyl)-amine 160[6-(3-Dimethylamino-propoxy)-2,4-dihydro- 94.5 0.05855indeno[1,2-c]pyrazol-3-yl]-(3-fluoro-phenyl)-amine 161[6-(3-Dimethylamino-propoxy)-2,4-dihydro- 84 0.3825indeno[1,2-c]pyrazol-3-yl]-pyridin-3-yl-amine 162(2,5-Dimethoxy-phenyl)-[6-(3-dimethylamino- 21.5 54.87propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]- amine 163(2,5-Difluoro-phenyl)-[6-(3-dimethylamino-propoxy)- 32 22.652,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 165[6-(3-Dimethylamino-propoxy)-2,4-dihydro- 92.5 0.1009indeno[1,2-c]pyrazol-3-yl]-(3-trifluoromethyl-Phenyl)- amine 166(3-Chloro-4-fluoro-phenyl)-[7-methoxy-6-(3- 88 0.085methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol- 3-yl]-amine 167(3-Chloro-4-fluoro-phenyl)-(6,7-diisopropoxy-2,4- 92 0.5111dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 168(6,7-Diisopropoxy-2,4-dihydro-indeno[1,2-c]pyrazol- 91 0.06883-yl)-(3-methoxy-phenyl)-amine 169(6,7-Diisopropoxy-2,4-dihydro-indeno[1,2-c]pyrazol- 89 0.0363-yl)-(3-fluoro-phenyl)-amine 170(4-Fluoro-phenyl)-(7-methoxy-2,4-dihydro- 95.5 0.02676indeno[1,2-c]pyrazol-3-yl)-amine 171(7-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 92.5 0.1232(4-methoxy-phenyl)-amine 172 (3-Fluoro-phenyl)-(7-methoxy-2,4-dihydro-55 0.0133 indeno[1,2-c]pyrazol-3-yl)-amine 173(7-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 87 0.2146pyridin-3-yl-amine 174 (2,5-Dimethoxy-phenyl)-(7-methoxy-2,4-dihydro- 830.3459 indeno[1,2-c]pyrazol-3-yl)-amine 175(2,4-Dimethoxy-phenyl)-(7-methoxy-2,4-dihydro- 71 3.929indeno[1,2-c]pyrazol-3-yl)-amine 176(2,5-Difluoro-phenyl)-(7-methoxy-2,4-dihydro- 46.5 0.3183indeno[1,2-c]pyrazol-3-yl)-amine 177(7-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 65.5 0.5226(4-trifluoromethoxy-phenyl)-amine 178(7-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 98.5 0.1324(4-trifluoromethyl-phenyl)-amine 179(3-Chloro-4-fluoro-phenyl)-[7-methoxy-6-(3- 92 0.07124morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2- c]pyrazol-3-yl]-amine180 (3-Fluoro-phenyl)-[7-methoxy-6-(3-pyrrolidin-1-yl- 98.5 0.0133propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]- amine 181(3-Chloro-4-fluoro-phenyl)-[7-methoxy-6-(3- 74.5 0.01536pyrrolidin-1-yl-propoxy)-2,4-dihydro-indeno[1,2- c]pyrazol-3-yl]-amine182 (3-Fluoro-phenyl)-(7-methyl-2,4-dihydro-indeno[1,2- 107 0.005c]pyrazol-3-yl)-amine 183 (4-Methoxy-phenyl)-(7-methyl-2,4-dihydro- 530.5455 indeno[1,2-c]pyrazol-3-yl)-amine 184(2,5-Dimethoxy-phenyl)-(7-methyl-2,4-dihydro- 94 1.1indeno[1,2-c]pyrazol-3-yl)-amine 185(2,5-Difluoro-phenyl)-(7-methyl-2,4-dihydro- 84 0.05indeno[1,2-c]pyrazol-3-yl)-amine 186(7-Methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4- 78 0.4141trifluoromethoxy-phenyl)-amine 187(7-Methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3- 35trifluoromethyl-phenyl)-amine 188(6-Chloro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 74 0.0437pyridin-3-yl-amine 189(6-Chloro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4- 92 0.1989methoxy-phenyl)-amine 190(6-Chloro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3- 80 0.04methoxy-phenyl)-amine 191(6-Chloro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3- 88 0.0686fluoro-phenyl)-amine 192(6-Chloro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 67 0.103(2,5-difluoro-phenyl)-amine 193(6-Chloro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4- 49trifluoromethyl-phenyl)-amine 194(6-Chloro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4- 87 2.608trifluoromethoxy-phenyl)-amine 195(3,5-Bis-trifluoromethyl-phenyl)-(6-chloro-2,4- 76 2.28dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 196N-(6-Chloro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 70 1.293N′,N′-dimethyl-benzene-1,4-diamine 197(6-Chloro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-m- 8 tolyl-amine 198(6-Chloro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-p- 72 0.1384tolyl-amine 199 [6-(3-Dimethylamino-propoxy)-7-methoxy-2,4- 83 0.0059dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-fluoro-phenyl)- amine 200(3-Chloro-4-fluoro-phenyl)-[6-(3-dimethylamino- 87 0.002propoxy)-7-methoxy-2,4-dihydro-indeno[1,2- c]pyrazol-3-yl]-amine 201(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4- 96 0.009fluoro-phenyl)-amine 202(3-Chloro-4-fluoro-phenyl)-(6-fluoro-2,4-dihydro- 77 0.01238indeno[1,2-c]pyrazol-3-yl)-amine 203(2,5-Dimethoxy-phenyl)-(6-fluoro-2,4-dihydro- 86 0.01595indeno[1,2-c]pyrazol-3-yl)-amine 204(3,5-Dimethoxy-phenyl)-(6-fluoro-2,4-dihydro- 90 0.038indeno[1,2-c]pyrazol-3-yl)-amine 205(3,4-Dimethoxy-phenyl)-(6-fluoro-2,4-dihydro- 86 0.047indeno[1,2-c]pyrazol-3-yl)-amine 206(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 63 0.6401yl)-(3,5-dimethyl-phenyl)-amine 207(3,5-Difluoro-phenyl)-(6,7-dimethoxy-2,4-dihydro- 89 0.01indeno[1,2-c]pyrazol-3-yl)-amine 208(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 82 0.003yl)-(3-methylsulfanyl-phenyl)-amine 209(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 99 0.03281yl)-(3-ethyl-phenyl)-amine 2103-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol- 90 0.067233-ylamino)-benzoic acid ethyl ester 211(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 87 0.05yl)-(3-trifluoromethylsulfanyl-phenyl)-amine 212(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 84 0.775yl)-(4-fluoro-3-trifluoromethyl-phenyl)-amine 213(3-Chloro-phenyl)-{7-methoxy-6-[3-(4-methyl- 82 0.0027piperazin-1-yl)-propoxy]-2,4-dihydro-indeno[1,2- c]pyrazol-3-yl}-amine214 (3-Chloro-4-fluoro-phenyl)-{7-methoxy-6-[3-(4- 46methyl-piperazin-1-yl)-propoxy]-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl}-amine 215{7-Methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]- 99 0.00572,4-dihydro-indeno[1,2-c]pyrazol-3-yl}-(3-methoxy- phenyl)-amine 216(3-Fluoro-phenyl)-{7-methoxy-6-[3-(4-methyl- 100 0.0058piperazin-1-yl)-propoxy]-2,4-dihydro-indeno[1,2- c]pyrazol-3-yl}-amine217 [6-(3-Dimethylamino-propoxy)-2,4-dihydro- 51 3.479indeno[1,2-c]pyrazol-3-yl]-(4-trifluoromethoxy- phenyl)-amine 218(4-Benzyloxy-phenyl)-(6,7-dimethoxy-2,4-dihydro- 81 2.01indeno[1,2-c]pyrazol-3-yl)-amine 219(3,4-Dichloro-benzyl)-(6,7-dimethoxy-2,4-dihydro- 39indeno[1,2-c]pyrazol-3-yl)-amine 220Cyclohexylmethyl-(6,7-dimethoxy-2,4-dihydro- 73 3.29indeno[1,2-c]pyrazol-3-yl)-amine 221(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 71 1.598yl)-[4-(piperidine-4-sulfonyl)-phenyl]-amine 222(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 70 0.806yl)-(4-methyl-benzyl)-amine 223(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 97 0.04593yl)-(2-methyl-benzyl)-amine 224(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 24yl)-(2-methoxy-benzyl)-amine 225(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 90 0.07443yl)-(3-methoxy-benzyl)-amine 226(3-Fluoro-phenyl)-[6-(3-imidazol-1-yl-propoxy)-7- 102 0.003methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]- amine 227(3-Chloro-4-fluoro-phenyl)-[6-(3-imidazol-1-yl- 83.5 0.03487propoxy)-7-methoxy-2,4-dihydro-indeno[1,2- c]pyrazol-3-yl]-amine 230(2-Chloro-benzyl)-(6,7-dimethoxy-2,4-dihydro- 90 0.0019indeno[1,2-c]pyrazol-3-yl)-amine 231(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 37yl)-(4-methoxy-benzyl)-amine 232(5,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen- 102 0.03966-yl)-(3-methoxy-phenyl)-amine 233(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4- 50 0.02759methoxy-phenyl)-amine 234(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3- 101 0.3581methoxy-phenyl)-amine 235(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3- 86 0.2114fluoro-phenyl)-amine 236 (2,5-Difluoro-phenyl)-(6-fluoro-2,4-dihydro- 820.005 indeno[1,2-c]pyrazol-3-yl)-amine 237(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4- 88 0.05trifluoromethyl-phenyl)-amine 238(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4- 87 0.4187trifluoromethoxy-phenyl)-amine 239(3,5-Bis-trifluoromethyl-phenyl)-(6-fluoro-2,4- 91 0.138dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 240(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-m- 92 0.002 tolyl-amine242 (3-Fluoro-phenyl)-[7-methoxy-6-(3-methoxy- 104 0.013propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]- amine 244[7-Methoxy-6-(3-methoxy-propoxy)-2,4-dihydro- 101 0.0002indeno[1,2-c]pyrazol-3-yl]-(3-methoxy-phenyl)-amine 245(6,7-Diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 87 0.001(3-methoxy-phenyl)-amine 246(3-Chloro-4-fluoro-phenyl)-(6,7-dioethoxy-2,4- 77 0.0121dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 247(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2- 96 0.07c]pyrazol-3-yl)-phenyl-amine 248(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2- 68 0.4099c]pyrazol-3-yl)-(4-fluoro-phenyl)-amine 249(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2- 96 0.006c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine 250(3-Chloro-4-fluoro-phenyl)-(6,7-dimethoxy-4-methyl- 88 0.22342,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 251(3,5-Difluoro-phenyl)-(6,7-dimethoxy-4-methyl-2,4- 84 0.3222dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 252(2,5-Difluoro-phenyl)-(6,7-dimethoxy-4-methyl-2,4- 16dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 253(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2- 94 0.0165c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine 254(3-Benzyloxy-phenyl)-(6,7-dimethoxy-4-methyl-2,4- 89 0.1808dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 255(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2- 90 0.1615c]pyrazol-3-yl)-(3-methylsulfanyl-phenyl)-amine 256 (3-Bromo-phenyl)-(6,7-dimethoxy-4-methyl-2,4- 89 0.008dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 257 (3-Chloro-phenyl)-(6,7-dimethoxy-4-methyl-2,4- 35dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 258(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2- 39c]pyrazol-3-yl)-(2,5-dimethoxy-phenyl)-amine 2593-[3-(3-Chloro-phenylamino)-7-methoxy-2,4-dihydro- 93 0.002045indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol 2603-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4- 91 0.0015dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2- diol 2613-[3-(3-Chloro-4-fluoro-phenylamino)-7-methoxy- 71 0.012,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane- 1,2-diol 2623-[3-(3-Fluoro-phenylamino)-7-methoxy-2,4-dihydro- 90 0.001indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol 2633-[7-Methoxy-3-(pyridn-3-ylamino)-2,4-dihydro- 103 0.046indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol 264Benzyl-(6,7-diethoxy-2,4-dihydro-indeno[1,2- 86 0.08519c]pyrazol-3-yl)-amine 2653-[3-(3-Fluoro-phenylamino)-7-methoxy-2,4-dihydro- 63 0.005535indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol 2663-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4- 110 0.001534dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol 2673-[3-(3-Choloro-4-fluoro-phenylamino)-7-methoxy- 93.5 0.010592,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1- ol 2683-[3-(3-Chloro-phenylamino)-7-methoxy-2,4-dihydro- 84 0.001134indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol 2691-[3-(3-Fluoro-phenylamino)-7-methoxy-2,4-dihydro- 94 0.0005914indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl- propan-2-ol 2701-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4- 107 0.0004287dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1- yl-propan-2-ol 271(3,5-Dichloro-benzyl)-(6,7-dimethoxy-2,4-dihydro- 54.5 6.987indeno[1,2-c]pyrazol-3-yl)-amine 272(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 61 0.3888yl)-(3-methyl-benzyl)-amine 273(3-Chloro-4-methyl-benzyl)-(6,7-dimethoxy-2,4- 77 1.584dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 274(2,5-Dimethoxy-benzyl)-(6,7-dimethoxy-2,4-dihydro- 57.5 2.61indeno[1,2-c]pyrazol-3-yl)-amine 275(3,4-Difluoro-benzyl)-(6,7-dimethoxy-2,4-dihydro- 80.5 0.5006indeno[1,2-c]pyrazol-3-yl)-amine 276(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 11 0.2874yl)-(4-fluoro-3-nitro-phenyl)-amine 277(3-Chloro-4-methoxy-phenyl)-(6,7-dimethoxy-2,4- 88 1.361dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 2781-[3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2- 97 0.02949c]pyrazol-3-ylamino)-phenyl]-ethanol 279(3,5-Di-tert-butyl-phenyl)-(6,7-dimethoxy-2,4- 19.5 203.1dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 2801-[3-(3-Chloro-4-fluoro-phenylamino)-7-methoxy- 102 0.001722,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3- pyrrolidin-1-yl-propan-2-ol281 1-[7-Methoxy-3-(pyridin-3-ylamino)-2,4-dihydro- 67 0.002599indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl- propan-2-ol 2821-[3-(3-Chloro-phenylamino)-7-methoxy-2,4-dihydro- 99 0.000089indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl- propan-2-ol 283[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro 86.5 0.004356indeno[1,2-c]pyrazol-3-yl]-(3-fluoro-phenyl)-amine 284[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro 84.6 0.00509indeno[1,2-c]pyrazol-3-yl]-(3-methoxy-phenyl)-amine 285[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro 18.5 0.002779indeno[1,2-c]pyrazol-3-yl]-(3-chloro-phenyl)-amine 286[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro- 95.5 0.01624indeno[1,2-c]pyrazol-3-yl]-pyridin-3-yl-amine 287[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro- 92.5 0.02616indeno[1,2-c]pyrazol-3-yl]-(3-Chloro-4-fluoro-phenyl)- amine 288(3-Chloro-4-methoxy-phenyl)-(6-fluoro-2,4-dihydro- 88.5 0.2194indeno[1,2-c]pyrazol-3-yl)-amine 2891-[3-(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3- 93.5 0.01853ylamino)-phenyl]-ethanol 290(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 87.5 0.06142(1H-indol-5-yl)-amine 291 (6-Benzyloxy-7-methoxy-2,4-dihydro-indeno[1,2-95 0.2052 c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine 292 (2-Chloro-benzyl)-(6,7-diethoxy-2,4-dihydro- 86.5 0.01822indeno[1,2-c]pyrazol-3-yl)-amine 293(6,7-Diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 96.5 0.06916(2-fluoro-benzyl)-amine 294(6,7-Diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 81 0.2637(3-fluoro-benzyl)-amine 295(2,6-Dichloro-benzyl)-(6,7-diethoxy-2,4-dihydro- 81.5 0.001645indeno[1,2-c]pyrazol-3-yl)-amine 296(6,7-Diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 72.5 1.821(2-methoxy-benzyl)-amine 2973-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol- 90.5 0.27493-ylamino)-N-(2-hydroxy-ethyl)-benzamide 2983-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol- 92 0.40823-ylamino)-N-(3-pyrrolidin-1-yl-propyl)-benzamide 299(7-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 80 0.01928phenyl-amine 300 (6,7-Dimethoxy-4-phenyl-2,4-dihydro-indeno[1,2- 40c]pyrazol-3-yl)-phenyl-amine 301(6,7-Diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 72(2-trifluoromethoxy-benzyl)-amine 302(6,7-Dimethoxy-4-phenyl-2,4-dihydro-indeno[1,2- 47c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine 303(3,5-Di-tert-butyl-phenyl)-(6-fluoro-2,4-dihydro- 50 9.338indeno[1,2-c]pyrazol-3-yl)-amine 304(3,5-Dichloro-benzyl)-(6-fluoro-2,4-dihydro- 38 3.456indeno[1,2-c]pyrazol-3-yl)-amine 305(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3- 87 0.4577methyl-benzyl)-amine 306(3-Chloro-4-methyl-benzyl)-(6-fluoro-2,4-dihydro 47.5 8.589indeno[1,2-c]pyrazol-3-yl)-amine 307(2,5-Dimethoxy-benzyl)-(6-fluoro-2,4-dihydro- 59 3.401indeno[1,2-c]pyrazol-3-yl)-amine 308(3,4-Difluoro-benzyl)-(6-fluoro-2,4-dihydro- 14 0.5108indeno[1,2-c]pyrazol-3-yl)-amine 309(3-Chloro-4-methoxy-phenyl)-(7-methyl-2,4-dihydro- 92.5 0.03022indeno[1,2-c]pyrazol-3-yl)-amine 3101-[3-(7-Methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3- 95.5 0.0202ylamino)-phenyl]-ethanol 311(1H-Indol-5-yl)-(7-methyl-2,4-dihydro-indeno[1,2- 68.5 0.07478c]pyrazol-3-yl)-amine 312(3,5-Di-tert-butyl-phenyl)-(7-methyl-2,4-dihydro- 56.5 5.672indeno[1,2-c]pyrazol-3-yl)-amine 313(3,5-Dichloro-benzyl)-(7-methyl-2,4-dihydro- 62.5 3.503indeno[1,2-c]pyrazol-3-yl)-amine 314(3-Methyl-benzyl)-(7-methyl-2,4-dihydro-indeno[1,2- 76 0.8944c]pyrazol-3-yl)-amine 315(3-Chloro-4-methyl-benzyl)-(7-methyl-2,4-dihydro- 17.5 1.924indeno[1,2-c]pyrazol-3-yl)-amine 316(2,5-Dimethoxy-benzyl)-(7-methyl-2,4-dihydro- 66 4.906indeno[1,2-c]pyrazol-3-yl)-amine 317(3,4-Difluoro-benzyl)-(7-methyl-2,4-dihydro- 79 1.247indeno[1,2-c]pyrazol-3-yl)-amine 318(4,5-Dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-3- 23 34.38yl)-phenyl-amine 319 [3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-80.5 2.201 3-ylamino)-phenyl]-(4-methyl-piperazin-1-yl)- methanone 320(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 70.5 1.958yl)-(3,4-dimethyl-benzyl)-amine 321(2,6-Difluoro-benzyl)-(6,7-dimethoxy-2,4-dihydro- 77 0.007454indeno[1,2-c]pyrazol-3-yl)-amine 322 (2,3-Dimethoxy-benzyl)-(6,7-dimethoxy-2,4-dihydro- 22 0.05466indeno[1,2-c]pyrazol-3-yl)-amine 323(2,5-Difluoro-benzyl)-(6,7-dimethoxy-2,4-dihydro- 60.5 8.711indeno[1,2-c]pyrazol-3-yl)-amine 324(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 74.5 1.325yl)-[1-(3-methoxy-phenyl)-ethyl]-amine 325(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 61 0.09669yl)-(2-fluoro-benzyl)-amine 326(2,3-Dichloro-benzyl)-(6,7-dimethoxy-2,4-dihydro- 82 0.2671indeno[1,2-c]pyrazol-3-yl)-amine 327(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 52 10.62yl)-(3-fluoro-benzyl)-amine 328(2,4-Difluoro-benzyl)-(6,7-dimethoxy-2,4-dihydro- 78.5 0.6971indeno[1,2-c]pyrazol-3-yl)-amine 329(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 58 0.0762yl)-(2-trifluoromethyl-benzyl)-amine 330(2,5-Dichloro-benzyl)-(6,7-dimethoxy-2,4-dihydro- 100 0.0162indeno[1,2-c]pyrazol-3-yl)-amine 331(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 93 0.1886yl)-(4-fluoro-benzyl)-amine 332(5,8-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 90 0.3716yl)-phenyl-amine 333 (3-Chloro-benzyl)-(6,7-dimethoxy-4-methyl-2,4- 73.52.55 dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 334(7-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3- 99.5 0.008693fluoro-phenyl)-amine 335(5,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen- 100 0.12926-yl)-(3-fluoro-phenyl)-amine 337(2,4-Dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro- 100 0.008804phenyl)-amine 338 (5-Chloro-2-methyl-phenyl)-(2,4-dihydro-indeno[1,2-78.5 0.4512 c]pyrazol-3-yl)-amine 339(2,5-Difluoro-phenyl)-(2,4-dihydro-indeno[1,2- 100 0.1174c]pyrazol-3-yl)-amine 340(2,4-Dihydro-indeno[1,2-c]pyrazol-3-yl)-(2-fluoro-5- 92.5 0.1046trifluoromethyl-phenyl)-amine 341(2,4-Dihydro-indeno[1,2-c]pyrazol-3-yl)-(2,5- 92.5 0.04118dimethoxy-phenyl)-amine 342 (5-Chloro-2-methoxy-phenyl)-(2,4-dihydro-56.5 0.02668 indeno[1,2-c]pyrazol-3-yl)-amine 343(2,4-Dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy- 99.5 0.008075phenyl-amine 344 (6,7-Diethoxy-4-methyl-2,4-dihydro-indeno[1,2- 1000.06465 c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine 345(6,7-Diethoxy-4-methyl-2,4-dihydro-indeno[1,2- 88 0.0893c]pyrazol-3-yl)-pyridin-3-yl-amine 346(3-Bromo-phenyl)-(6,7-diethoxy-4-methyl-2,4- 98 0.07392dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 347(3-Chloro-4-fluoro-phenyl)-(6,7-diethoxy-4-methyl- 90.5 0.54532,4-dihydro-indeno]1,2-c]pyrazol-3-yl)-amine 348(6,7-Diethoxy-4-methyl-2,4-dihydro-indeno[1,2- 97.5 0.02529c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine 349(6,7-Diethoxy-4-methyl-2,4-dihydro-indeno[1,2- 78 0.08089c]pyrazol-3-yl)-(4-fluoro-phenyl)-amine 3503-Phenylamino-4,5-dihydro-2H-benzo[g]indazole-7- 91 0.6512 carbonitrile351 (6,7-Diisopropoxy-4-methyl-2,4-dihydro-indeno[1,2- 93 0.3998c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine 352(6,7-Diisopropoxy-4-methyl-2,4-dihydro-indeno[1,2- 86.5 0.7554c]pyrazol-3-yl)-pyridin-3-yl-amine 353(3-Bromo-phenyl)-(6,7-diisopropoxy-4-methyl-2,4- 88 0.3594dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 354(3-Chloro-4-fluoro-phenyl)-(6,7-diisopropoxy-4- 62 2.45methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 355(6,7-Diisopropoxy-4-methyl-2,4-dihydro-indeno[1,2- 85 1.026c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine 356(6,7-Diisopropoxy-4-methyl-2,4-dihydro-indeno[1,2- 70 1.953c]pyrazol-3-yl)-(4-fluoro-phenyl)-amine 357(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2- 98.5 0.009417c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine 358(3-Bromo-phenyl)-(6-fluoro-7-methoxy-2,4-dihydro- 92 0.00877indeno[1,2-c]pyrazol-3-yl)-amine 359(3-Chloro-4-fluoro-phenyl)-(6-fluoro-7-methoxy-2,4- 98.5 0.04151dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 360(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2- 98 0.007501c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine 361(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2- 100 0.01156c]pyrazol-3-yl)-(4-fluoro-phenyl)-amine 3623-(3-Fluoro-phenylamino)-2,4-dihydro-indeno[1,2- 80.5 0.7844c]pyrazole-6,7-diol 363 3-(3-Fluoro-phenylamino)-7-methoxy-2,4-dihydro-76.5 0.005466 indeno[1,2-c]pyrazol-6-ol 364(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2- 100 0.01506c]pyrazol-3-yl)-pyridin-3-yl-amine 3653-[6-Ethoxy-3-(3-fluoro-phenylamino)-2,4-dihydro- 99.5 0.01131indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol 3663-[6-Ethoxy-3-(3-methoxy-phenylamino)-2,4- 100 0.01209dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol 3673-[3-(3-Chloro-phenylamino)-6-ethoxy-2,4-dihydro- 97 0.00814indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol 3683-[3-(3-Chloro-4-fluoro-phenylamino)-6-ethoxy-2,4- 89.5 0.06293dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol 369(6-Bromo-7-methoxy-2,4-dihydro-indeno[1,2- 100 0.0187c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine 370(6-Bromo-7-methoxy-2,4-dihydro-indeno[1,2- 94 0.01218c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine 3713-[6-Ethoxy-3-(pyridin-3-ylamino)-2,4-dihydro- 100 0.0476indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol 3723-[7-(3-Hydroxy-propoxy)-3-(pyridin-3-ylamino)-2,4- 100 0.01553dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol 3733-[3-(3-Chloro-phenylamino)-7-(3-hydroxy-propoxy)- 100 0.0037722,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1- ol 374(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 100 0.01412yl)-(3-ethoxy-phenyl)-amine 375(6,7-Diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 96.5 0.1028(3-ethoxy-phenyl)-amine 376 3-[3-(3-Ethoxy-phenylamino)-7-methoxy-2,4-100 0.009096 dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol 377(2-Chloro-pyridin-3-yl)-(6,7-dimethoxy-2,4-dihydro- 99 0.008572indeno[1,2-c]pyrazol-3-yl)-amine 378(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(2- 94.5 0.467methyl-benzyl)-amine 379 3-[3-(3-Ethoxy-phenylamino)-7-methoxy-2,4- 1000.008119 dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2- diol 380(3-Fluoro-phenyl)-(2H-8-oxa-2,3-diaza- 99.5 0.01533cyclopenta[a]inden-1-yl)-amine 381(3-Chloro-4-fluoro-phenyl)-(2H-8-oxa-2,3-diaza- 100 0.05492cyclopenta[a]inden-1-yl)-amine 3823-[7-Ethoxy-3-(3-fluoro-phenylamino)-2,4-dihydro- 100 0.01185indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol 3833-[7-Ethoxy-3-(pyridin-3-ylamino)-2,4-dihydro- 93 0.02533indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol 3843-[7-Ethoxy-3-(3-methoxy-phenylamino)-2,4- 100 0.005607dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol 3853-[3-(2-Chloro-benzylamino)-7-methoxy-2,4-dihydro- 98.5 0.004072indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol 3863-[3-(2-Fluoro-benzylamino)-7-methoxy-2,4-dihydro- 95.5 0.01101indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol 3873-[3-(2-Fluoro-benzylamino)-7-methoxy-2,4-dihydro- 100 0.01162indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol 3883-[6-Ethoxy-3-(3-ethoxy-phenylamino)-2,4-dihydro- 96 0.03667indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol 3893-[3-(3-Chloro-4-fluoro-phenylamino)-7-(3-hydroxy- 98 0.01511propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]- propan-1-ol 3901-[3-(2,6-Dichloro-benzylamino)-7-methoxy-2,4- 99 0.002029dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1- yl-propan-2-ol 3911-[3-(2,6-Difluoro-benzylamino)-7-methoxy-2,4- 99 0.006796dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1- yl-propan-2-ol 392(3-Chloro-phenyl)-[5-(3-morpholin-4-yl-propoxy)-2,4- 80 0.1528dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 393(3-Fluoro-phenyl)-[5-(3-morpholin-4-yl-propoxy)-2,4- 94.5 0.1737dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 394(3-Ethoxy-phenyl)-[5-(3-morpholin-4-yl-propoxy)-2,4- 91 0.3289dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 3953-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 88 0.6861indeno[1,2-c]pyrazole-2-carboxylic acid (3-fluoro- phenyl)-amide 3961-[3-(2-Chloro-benzylamino)-7-methoxy-2,4-dihydro- 99.5 0.005129indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl- propan-2-ol 3971-[3-(2-Fluoro-benzylamino)-7-methoxy-2,4-dihydro- 92 0.007701indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl- propan-2-ol 3983-[3-(3-Fluoro-phenylamino)-7-(3-hydroxy-propoxy)- 96 0.006822,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1- ol 4003-[7-(3-Hydroxy-propoxy)-3-(3-methoxy- 98.5 0.002918phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6- yloxy]-propan-1-ol 4013-[3-(3-Ethoxy-phenylamino)-7-(3-hydroxy-propoxy)- 98.5 0.022032,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1- ol 402(5,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen- 90 0.19576-yl)-pyridin-3-yl-amine 403(3-Chloro-phenyl)-(5,7-dihydro-1-thia-4,5-diaza- 96 0.08588cyclopenta[a]pentalen-6-yl)-amine 404(3-Chloro-4-fluoro-phenyl)-(5,7-dihydro-1-thia-4,5- 74.5 1.115diaza-cyclopenta[a]pentalen-6-yl)-amine 405(5,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen- 94.5 0.063546-yl)-(3-ethoxy-phenyl)-amine 4061-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 96 0.07502indeno[1,2-c]pyrazol-2-yl]-ethanone 407{[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 39 9.883indeno[1,2-c]pyrazole-2-carbonyl]-amino}-acetic acid ethyl ester 4082,2-Dimethyl-propionic acid 3-(3-fluoro- 83 0.6866phenylamino)-6,7-dimethoxy-4H-indeno[1,2- c]pyrazol-2-ylmethyl ester 4092,2-Dimethyl-propionic acid 3-(3-fluoro- 85.5 0.1076phenylamino)-6,7-dimethoxy-4H-indeno[1,2- c]pyrazol-1-ylmethyl ester 410(2-Bromo-3-fluoro-phenyl)-(6,7-dimethoxy-2,4- 83.5 1.076dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 4113-[(6,7-Dimethoxy-3-phenlylamino-4H-indeno[1,2- 14.5 0.08233c]pyrazole-2-carbonyl)-amino]-propionic acid ethyl ester 4122-{[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 44 12.72indeno[1,2-c]pyrazole-2-carbonyl]-amino}-4-methyl- pentanoic acid methylester 413 2-{[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 71 1.14indeno[1,2-c]pyrazole-2-carbonyl]-amino}-3-methyl- butyric acid methylester 414 (2,6-Difluoro-benzyl)-[5-(3-morpholin-4-yl-propoxy)- 80.50.5639 2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 415(2,6-Dichloro-benzyl)-[5-(3-morpholin-4-yl-propoxy)- 98 0.025812,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 416(2-Fluoro-benzyl)-[5-(3-morpholin-4-yl-propoxy)-2,4- 72.5 1.185dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 417(5-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 27.5 12.2(3-methoxy-5-trifluoromethyl-phenyl)-amine 4183-(5-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 82.5 0.8916ylamino)-benzenesulfonamide 419(3-Chloro-phenyl)-(4-ethyl-6,7-dimethoxy-2,4- 100 0.06214dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 420(3-Bromo-phenyl)-(4-ethyl-6,7-dimethoxy-2,4- 100 0.05236dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 421(4-Ethyl-6,7-dimethoxy-2,4-dihydro-indeno[1,2- 100 0.08219c]pyrazol-3-yl)-(3-fluoro-phenyl )-amine 422(3-Fluoro-phenyl)-(5-methoxy-2,4-dihydro- 83 0.02966indeno[1,2-c]pyrazol-3-yl)-amine 423(2,6-Difluoro-benzyl)-(5-methoxy-2,4-dihydro- 90 0.1815indeno[1,2-c]pyrazol-3-yl)-amine 424(3-Chloro-benzyl)-(6,7-dimethoxy-2,4-dihydro- 100 0.07912indeno[1,2-c]pyrazol-3-yl )-amine 425(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2- 96 0.002296c]pyrazol-3-yl)-(2-methyl-benzyl)-amine 426(2-Fluoro-benzyl)-(6-fluoro-7-methoxy-2,4-dihydro- 97 0.2415indeno[1,2-c]pyrazol-3-yl)-amine 427[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 80 1.15indeno[1,2-c]pyrazol-1-yl]-phenyl-methanone 4284-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 85.5 0.432indeno[1,2-c]pyrazol-1-yl]-4-oxo-butyric acid methyl ester 4294-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 72 0.6706indeno[1,2-c]pyrazol-1-yl]-4-oxo-butyric acid ethyl ester 4301-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 61.5 0.571indeno[1,2-c]pyrazol-1-yl]-propan-1-one 4311-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 84.5 0.4437indeno[1,2-c]pyrazol-1-yl]-2-methyl-propan-1-one 4321-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 95.5 0.03804indeno[1,2-c]pyrazol-1-yl]-2-hydroxy-ethanone 4333-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 71 0.5849indeno[1,2-c]pyrazole-1-carboxylic acid phenyl ester 4343-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 86 0.503indeno[1,2-c]pyrazole-2-carboxylic acid methyl ester 4353-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 67 1.588indeno[1,2-c]pyrazole-2-carboxylic acid ethyl ester 4363-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 9.5 0.9619indeno[1,2-c]pyrazole-2-carboxylic acid isopropyl ester 4373-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 83.5 0.2914indeno[1,2-c]pyrazole-2-carboxylic acid 2-methoxy- ethyl ester 4383-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 77.5 0.9923indeno[1,2-c]pyrazole-1-carboxylic acid 2-methoxy- ethyl ester 4393-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 69.5 0.6202indeno[1,2-c]pyrazole-1-carboxylic acid methyl ester 4403-[3-(3-Chloro-phenylamino)-2,4-dihydro- 89.5 0.04574indeno[1,2-c]pyrazol-5-yloxy]-propan-1-ol 4413-[3-(3-Ethoxy-phenylamino)-2,4-dihydro- 96 0.2058indeno[1,2-c]pyrazol-5-yloxy]-propan-1-ol 4423-[3-(3-Fluoro-phenylamino)-2,4-dihydro-indeno[1,2- 94.5 0.2048c]pyrazol-5-yloxy]-propan-1-ol 4433-[3-(2,6-Difluoro-benzylamino)-2,4-dihydro- 89.5 0.09795indeno[1,2-c]pyrazol-5-yloxy]-propan-1-ol 4443-[3-(2-Fluoro-benzylamino)-2,4-dihydro-indeno[1,2- 79.5 0.5185c]pyrazol-5-yloxy]-propan-1-ol 4453-[3-(2-Methyl-benzylamino)-2,4-dihydro-indeno[1,2- 95 0.02526c]pyrazol-5-yloxy]-propan-1-ol 446[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 93.5 0.2656indeno[1,2-c]pyrazol-1-yl]-phosphonic acid diethyl ester 4473-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 7indeno[1,2-c]pyrazole-1-sulfonic acid dimethylamide 4483-[3-(2,6-Dichloro-benzylamino)-7-methoxy-2,4- 100 0.001767dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol 4493-[3-(2,6-Difluoro-benzylamino)-7-methoxy-2,4- 98.5 0.004098dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol 4503-[3-(2,6-Dichloro-benzylamino)-7-methoxy-2,4- 100 0.0009382dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2- diol 4513-[3-(2-Chloro-benzylamino)-7-methoxy-2,4-dihydro- 99.5 0.002004indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol 452N1-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2- 72 1.096c]pyrazol-3-yl)-4-methyl-N3-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-1,3-diamine 453(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 88 0.8294yl)-(4-methoxy-pyridin-3-yl)-amine 454(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 99 0.2579yl)-(2,4-dimethoxy-pyridin-3-yl)-amine 455(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 95 0.1532yl)-(5-phenyl-isoxazol-3-ylmethyl)-amine 4573-[3-(2,6-Difluoro-benzylamino)-7-methoxy-2,4- 100 0.003414dihydro-indeno[1,2-c]pyrazol-6-yloxy]-Propane-1,2- diol 458[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 70.5 6.998indeno[1,2-c]pyrazol-1-yl]-(4-methoxy-phenyl)- methanone 4593-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 100 0.03654indeno[1,2-c]pyrazol-1-yl]-3-oxo-propionic acid ethyl ester 4601-[6-Ethoxy-3-(3-fluoro-phenylamino)-2,4-dihydro- 97.5 0.00427indeno[1,2-c]pyrazol-7-yloxy]-3-pyrrolidin-1-yl- propan-2-ol 4611-[6-Ethoxy-3-(pyridin-3-ylamino)-2,4-dihydro- 97.5 0.007552indeno[1,2-c]pyrazol-7-yloxy]-3-pyrrolidin-1-yl- propan-2-ol 4621-[6-Ethoxy-3-(3-methoxy-phenylamino)-2,4- 99 0.00215dihydro-indeno[1,2-c]pyrazol-7-yloxy]-3-pyrrolidin-1- yl-propan-2-ol 4631-[6-Ethoxy-3-(3-ethoxy-phenylamino)-2,4-dihydro- 98.5 0.01095indeno[1,2-c]pyrazol-7-yloxy]-3-pyrrolidin-1-yl- propan-2-ol 4645-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 92 0.2446indeno[1,2-c]pyrazol-1-yl]-5-oxo-pentanoic acid methyl ester 4651-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 96 0.006728indeno[1,2-c]pyrazol-1-yl]-2-methoxy-ethanone 4664-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 96 0.03113indeno[1,2-c]pyrazol-1-yl]-4-oxo-butyric acid 467 Acetic acid2-[3-(3-fluoro-phenylamino)-6,7- 96.5 0.01763dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-2-oxo-ethyl ester 4683-[3-(3-Bromo-phenylamino)-2,4-dihydro-indeno[1,2- 95.5 0.04784c]pyrazol-5-yloxy]-propane-1,2-diol 4693-[3-(3-Fluoro-phenylamino)-2,4-dihydro-indeno[1,2- 96 0.1598c]pyrazol-5-yloxy]-propane-1,2-diol 4703-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 96 0.197indeno[1,2-c]pyrazole-1-carboxylic acid 2- benzyloxy-ethyl ester 4713-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 90.5 0.1347indeno[1,2-c]pyrazole-1-carboxylic acid 2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethyl ester 472(6,7-Dimethoxy-1-methoxymethyl-1,4-dihydro- 35indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine 473 Methoxy-aceticacid 2-[3-(3-fluoro-phenylamino)- 98.5 0.0089626,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-2-oxo- ethyl ester 474Isobutyric acid 2-[3-(3-fluoro-phenylamino)-6,7- 91.5 0.06342dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-2-oxo-ethyl ester 475(6,7-Dimethoxy-2-methoxymethyl-2,4-dihydro- 65.5 5.035indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine 476(2,6-Difluoro-phenyl)-(6,7-dimethoxy-2,4-dihydro- 88.5 0.2495indeno[1,2-c]pyrazol-3-yl)-amine 477(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 95 0.2293yl)-(2,4,6-trifluoro-phenyl)-amine 478(3-Bromo-phenyl)-[5-(2-pyrrolidin-1-yl-ethoxy)-2,4- 93.5 0.1617dihydro-indeno[1,2-c]pyrazol-3-yl]-amine 4793-[3-(2,6-Dichloro-benzylamino)-2,4-dihydro- 94.5 0.6238indeno[1,2-c]pyrazol-5-yloxy]-propane-1,2-diol 480(2,6-Difluoro-phenyl)-[3-(3-fluoro-Phenylamino)-6,7- 8dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-methanone 481(2-Fluoro-phenyl)-[3-(3-fluoro-phenylamino)-6,7- 59 3.764dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-methanone 482(3-Bromo-phenyl)-(4-ethyl-6,7-dimethoxy-1,4- 100 0.03863dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 483(3-Bromo-phenyl)-(4-ethyl-6,7-dimethoxy-1,4- 78.5 4.97dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 4841-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 87 0.218indeno[1,2-c]pyrazol-1-yl]-propan-2-one 485(3-Bromo-phenyl)-(6,7-dimethoxy-4,4-dimethyl-2,4- 32 59.03dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 486(3-Chloro-phenyl)-(6,7-dimethoxy-4,4-dimethyl-2,4- 34.5 15.76dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 487(6,7-Dimethoxy-4,4-dimethyl-2,4-dihydro-indeno[1,2- 43 37.47c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine 488(6,7-Dimethoxy-4,4-dimethyl-2,4-dihydro-indeno[1,2- 33.5 39.29c]pyrazol-3-yl)-(3-methoxy-Phenyl)-amine 489(6,7-Dimethoxy-4,4-dimethyl-2,4-dihydro-indeno[1,2- 25.5c]pyrazol-3-yl)-(3-ethoxy-phenyl)-amine 490 Butyric acid3-(3-fluoro-phenylamino)-6,7- 96 0.0285dimethoxy-4H-indeno[1,2-c]pyrazol-1-ylmethyl ester 491 Butyric acid3-(3-fluoro-phenylamino)-6,7- 92 0.3142dimethoxy-4H-indeno[1,2-c]pyrazol-2-ylmethyl ester 492(4-Fluoro-phenyl)-[3-(3-fluoro-Phenylamino)-6,7- 78 0.4716dimethoxy-4H-indenol[1,2-c]pyrazol-1-yl]-methanone 494(4-Chloro-phenyl)-[3-(3-fluoro-Phenylamino)-6,7- 83 1.541dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-methanone 496 Acetic acid3-(3-fluoro-phenylamino)-6,7-dimethoxy- 88.5 0.01364H-indeno[1,2-c]pyrazol-1-ylmethyl ester 497 Acetic acid3-(3-fluoro-phenylamino)-6,7-dimethoxy- 97 0.077744H-indeno[1,2-c]pyrazol-2-ylmethyl ester 498 Acetic acid4-[3-(3-fluoro-phenylamino)-6,7- 51.5 8.326dimethoxy-4H-indeno[1,2-c]pyrazol-1-ylmethyl]- phenyl ester 499 Aceticacid 4-[3-(3-fluoro-phenylamino)-6,7- 87 1.743dimethoxy-4H-indeno[1,2-c]pyrazol-2-ylmethyl]- phenyl ester 5003-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 80.5 0.4923indeno[1,2-c]pyrazole-1-carboxylic acid 4-fluoro- phenyl ester 5013-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 90 0.09598indeno[1,2-c]pyrazole-1-carboxylic acid 4-chloro- phenyl ester 5021-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 60.5 54.02indeno[1,2-c]pyrazol-1-yl]-propan-2-ol 5033-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 103 0.04509indeno[1,2-c]pyrazole-2-carboxylic acid 4-fluoro- phenyl ester 504(6,7-Diethoxy-4-methyl-2,4-dihydro-indeno[1,2- 101 0.1419c]pyrazol-3-yl)-(3-ethoxy-Phenyl)-amine 505(3-Ethoxy-phenyl)-(4-ethyl-6,7-dimethoxy-2,4- 97 0.134dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 5065-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 97 0.0294indeno[1,2-c]pyrazol-1-yl]-5-oxo-pentanoic acid methylamide 509[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 30.5indeno[1,2-c]pyrazol-1-yl]-acetic acid methyl ester 510[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 57 26.62indeno[1,2-c]pyrazol-2-yl]-acetic acid ethyl ester 511[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 51 12.52indeno[1,2-c]pyrazol-1-yl]-acetic acid ethyl ester 512(4-Ethyl-6,7-dimethoxy-2,4-dihydro-indeno[1,2- 92 0.1834c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine 5133-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 86 0.7726indeno[1,2-c]pyrazole-1-carboxylic acid 2-chloro- phenyl ester 5141-[3-(3-Bromo-phenylamino)-4-ethyl-6,7-dimethoxy- 85 0.244H-indeno[1,2-c]pyrazol-1-yl]-2-methoxy-ethanone 5151-[3-(3-Bromo-phenylamino)-4-ethyl-6,7-dimethoxy- 90 0.13574H-indeno[1,2-c]pyrazol-2-yl]-2-methoxy-ethanone 5163-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 68.5 10.04indeno[1,2-c]pyrazole-1-carboxylic acid (2-amino- ethyl)-amide 5173-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 75.5 1.793indeno[1,2-c]pyrazole-1-carboxylic acid (2- dimethylamino-ethyl)-amide518 2-Benzyloxy-1-[3-(3-bromo-phenylamino)-4-ethyl- 92.5 0.18386,7-dimethoxy-4H-indeno[1,2-c]pyrazol-2-yl]- ethanone 5192-Benzyloxy-1-[3-(3-bromo-phenylamino)-4-ethyl- 97.5 0.1396,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]- ethanone 5203-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 100 0.06525indeno[1,2-c]pyrazole-1-carboxylic acid (2-pyrrolidin- 1-yl-ethyl)-amide521 3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 97 0.05587indeno[1,2-c]pyrazole-1-carboxylic acid (2- morpholin-4-yl-ethyl)-amide522 3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 94 0.7909indeno[1,2-c]pyrazole-2-carboxylic acid (2- morpholin-4-yl-ethyl)-amide523 3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 98.5 0.1927indeno[1,2-c]pyrazole-1-carboxylic acid [2-(2-hydroxy-ethylamino)-ethyl]-amide 5243-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 78 2.482indeno[1,2-c]pyrazole-1-carboxylic acid (2- methylamino-ethyl)-amide 5253-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 33 43.16indeno[1,2-c]pyrazole-1-carboxylic acid (2- isobutyrylamino-ethyl)-amide526 3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 73 8.091indeno[1,2-c]pyrazole-1-carboxylic acid (2- acetylamino-ethyl)-amide 5272-Methyl-acrylic acid 2-{[3-(3-fluoro-phenylamino)- 46.5 17.476,7-dimethoxy-4H-indeno[1,2-c]pyrazole-1- carbonyl]-amino}-ethyl ester528 2-Methyl-acrylic acid 2-{[3-(3-fluoro-phenylamino)- 93.5 0.1966,7-dimethoxy-4H-indeno[1,2-c]pyrazole-2- carbonyl]-amino}-ethyl ester529 6-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 44 10.64indeno[1,2-c]pyrazol-2-yl]-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid 5302-{[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 71.5 4.151indeno[1,2-c]pyrazole-1-carbonyl]-amino}-3-methyl- butyric acid methylester 531 4-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 90 0.02404indeno[1,2-c]pyrazol-1-yl]-4-oxo-butyramide 5323-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 42indeno[1,2-c]pyrazole-1-carboxylic acid (2- benzoylamino-ethyl)-amide534 2-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 94 0.9332indeno[1,2-c]pyrazol-1-yl]-acetamide 5351-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 105 0.03224indeno[1,2-c]pyrazol-2-yl]-3-pyrrolidin-1-yl-propane- 1,3-dione 5361-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 88 0.4362indeno[1,2-c]pyrazol-1-yl]-3-pyrrolidin-1-yl-propane- 1,3-dione 537N,N-Diethyl-3-[3-(3-fluoro-phenylamino)-6,7- 104 0.3303dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-3-oxo- propionamide 538(3-Bromo-phenyl)-(4-isopropyl-6,7-dimethoxy-2,4- 65dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 540(3-Chloro-phenyl)-(4-isopropyl-6,7-dimethoxy-2,4- 47 14.68dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 541(4-lsopropyl-6,7-dimethoxy-2,4-dihydro-indeno[1,2- 50 44.22c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine 5423-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 21indeno[1,2-c]pyrazole-1-carboxylic acid [2-(2-hydroxy-benzoylamino)-ethyl]-amide 5443-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 60indeno[1,2-c]pyrazole-1-carboxylic acid {2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethyl}-amide 546[3-(3-Bromo-phenylamino)-4-ethyl-6,7-dimethoxy- 72.54H-indeno[1,2-c]pyrazol-1-yl]-phenyl-methanone 5473-(3-Bromo-phenylamino)-4-ethyl-6,7-dimethoxy- 68.54H-indeno[1,2-c]pyrazole-1-carboxylic acid 2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethyl ester 5483-(3-Bromo-phenylamino)-6,7-dimethoxy-4-methyl- 82.5 0.21444H-indeno[1,2-c]pyrazole-1-carboxylic acid 2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethyl ester 549(7-Benzyloxy-6-methoxy-2,4-dihydro-indeno[1,2- 106 0.09114c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine 553(3-Bromo-phenyl)-(6,7-dimethoxy-4-methyl-2,4- 99.5 0.006501dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 554(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2- 102 0.0208c]pyrazol-3-yl)-(3-ethoxy-phenyl)-amine 555(3-Bromo-phenyl)-(4-ethyl-6,7-dimethoxy-2,4- 97.5 0.02094dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 556(3-Ethoxy-phenyl)-(4-ethyl-6,7-dimethoxy-2,4- 98 0.0104dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 557N-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-2,4- 101.5 0.03248dihydro-indeno[1,2-c]pyrazol-5-yl]-acetamide 558N3-(3-Fluoro-phenyl)-6,7-dimethoxy-2,4-dihydro- 102 0.01214indeno[1,2-c]pyrazole-3,5-diamine 559(2-Chloro-pyridin-3-yl)-(6,7-dimethoxy-4-methyl-2,4- 102 0.03706dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 560(4-Methoxy-2-methyl-6,9-dihydro-3-oxa-1,6,7-triaza- 102 0.02471cyclopenta[b]-as-indacen-8-yl)-(3-methoxy-Phenyl)- amine 562(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 93.5 0.08399yl)-pyridin-2-yl-amine 563(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 89 1.449yl)-pyridin-2-ylmethyl-amine 564(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 99.5 0.8864yl)-pyridin-3-ylmethyl-amine 565(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-(6,7-dimethoxy- 41.52,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 5663-(2,3-Dihydro-indol-1-yl)-6,7-dimethoxy-2,4- 54dihydro-indeno[1,2-c]pyrazole 5673-(5-Bromo-2,3-dihydro-indol-1-yl)-6,7-dimethoxy- 39.52,4-dihydro-indeno[1,2-c]pyrazole 568(3-Bromo-phenyl)-(6,7-dimethoxy-4-methyl-2,4- 78 0.7904dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 569(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2- 64 5.098c]pyrazol-3-yl)-(3-ethoxy-phenyl)-amine 570(3-Bromo-phenyl)-(4-ethyl-6,7-dimethoxy-2,4- 77.5 2.048dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 571(3-Ethoxy-phenyl)-(4-ethyl-6,7-dimethoxy-2,4- 66 3.886dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 5722-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 67 7.332indeno[1,2-c]pyrazol-1-yl]-ethanol 5732-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 52indeno[1,2-c]pyrazol-2-yl]-ethanol 574(2-Fluoro-benzyl)-(4-methoxy-2-methyl-6,9-dihydro- 99 0.1633-oxa-1,6,7-triaza-cyclopenta[b]-as-indacen-8-yl)- amine 575(2-Bromo-benzyl)-(6,7-dimethoxy-2,4-dihydro- 99.5 0.002129indeno[1,2-c]pyrazol-3-yl)-amine 576(5-Bromo-3-methyl-pyridin-2-yl)-(6,7-dimethoxy-2,4- 18 33.33dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 577(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 19 361.5yl)-(4-trifluoromethyl-pyridin-3-yl)-amine 5783-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 80 4.023indeno[1,2-c]pyrazole-1-carboxylic acid methylamide 5793-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 28indeno[1,2-c]pyrazole-2-carboxylic acid methylamide 5803-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 93 0.1255indeno[1,2-c]pyrazole-2-carbothioic acid methylamide 5813-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 90.5 1.139indeno[1,2-c]pyrazole-1-carbothioic acid methylamide 582(3-Bromo-pyridin-2-yl)-(6,7-dimethoxy-2,4-dihydro- 82.5 1.247indeno[1,2-c]pyrazol-3-yl)-amine 583(5-Bromo-pyridin-2-yl)-(6,7-dimethoxy-2,4-dihydro- 82 1.101indeno[1,2-c]pyrazol-3-yl)-amine 584(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 109 0.01113yl)-(3-isopropoxy-phenyl)-amine 585(2,6-Dichloro-benzyl)-(4-ethyl-6,7-dimethoxy-2,4- 101.5 0.4287dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 586(2,6-Dichloro-benzyl)-(6,7-dimethoxy-4-methyl-2,4- 100.5 0.02776dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 587(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 86 1.704yl)-(3-methyl-pyridin-2-yl)-amine 588(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3- 103 0.5564yl)-(4,6-dimethyl-pyridin-2-yl)-amine 5916-[(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol- 96 0.66233-yl)-(3-fluoro-phenyl)-amino]-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid 594(6,7-Diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)- 64 0.0156(3-fluoro-phenyl)-amine 595(7-Methoxy-2H-8-oxa-2,3-diaza-cyclopenta[a]inden- 71 0.024881-yl)-phenyl-amine 598 3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 098.43 indeno[1,2-c]pyrazole-2-carboxylic acid pentadecylamide 6013-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol- 89 2.293-ylamino)-N-{2-[2-(2-{2-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoylamino]-ethoxy}-ethoxy)-ethoxy]-ethyl}-benzamide 602[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 40indeno[1,2-c]pyrazol-2-yl]-acetic acid methyl ester 6043-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H- 79.5 2.127indeno[1,2-c]pyrazole-2-carboxylic acid {2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethyl}-amide 605(3-Fluoro-phenyl)-(4-methoxy-2-methyl-8a,9- 97.5 0.0051dihydro-3-oxa-1,6,7-triaza-cyclopenta[b]-as-indacen- 8-yl)-amine 6068-Benzyl-3-(3-fluoro-phenylamino)-6-methoxy-2,4- 53.5dihydro-indeno[1,2-c]pyrazol-7-ol 607(2-Chloro-pyridin-3-yl)-(4-ethyl-6,7-dimethoxy-2,4- 78 0.5475dihydro-indeno[1,2-c]pyrazol-3-yl)-amine 6083-(3-Fluoro-phenylamino)-6-methoxy-2,4-dihydro- 106 0.02596indeno[1,2-c]pyrazol-7-ol 609(6,7-Dimethoxy-1-methyl-1,4-dihydro-indeno[1,2- 84 4.683c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine 610(6,7-Dimethoxy-2-methyl-2,4-dihydro-indeno[1,2- 51.5 9.377c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine 6116-[3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid

[1502] 2. Inhibition of c-Abl Kinase Activity

[1503] Previous studies have shown that a selective PDGF-R kinaseinhibitor STI-571 (supra) was also a selective inhibitor for c-Ablkinase activity and therefore was a selective inhibitor for the Bcr-Abloncogene product (for a review on therapeutic interventions on Bcr-Ablsee Kindler et al., 2002, Expert Opin Ther Targets; 6(1): 85-101).Variants of Bcr-Abl have been associated with distinct types of humanleukemias, such as chronic myelogenous leukemia (CML); acute lymphocyticleukemia (ALL); chronic neutrophilic leukemia (CNL); acuteundifferentiated leukemia (AUL); and acute myelogenous leukemia (AML)(Anjali et al., 2002, Leukemia Research, 26(8): 713-720). The inhibitoryactivity of compounds within the scope of the invention on c-Abl kinaseactivity was tested according to the following procedure.

[1504] Materials

[1505] 1. 10× Kinase Buffer [500 mM Tris-HCl pH=8, 100 mM MgCl₂, 1 mMNa₃VO₄]

[1506] 2. 10 mM DTT [final concentration 1 mM]

[1507] 3. 10 mM ATP [final concentration 5 μM] (Gibco, Cat No:18330-019,Carlsbad, Calif.)

[1508] 4. ³³P-γ-ATP [NEG-602H; 2000-3000 Ci/mmol], 2 μCuries per well at10 μCi/μl (0.2 μl/well)

[1509] 5. Abl enzyme (New England Biolabs, Cat No. P6050L, Beverly,Mass.) at 100 Units/μl use 10 Units/well (0.1 μl/well)

[1510] 6. Enzyme Dilution Buffer [50 mM Tris-HCl pH=8.0, 0.1% BSA]

[1511] 7. Wash/Stop Buffer [PBS+100 mM EDTA]

[1512] 8. NEN Streptavidin Flashplates (New England Nuclear, Cat No.SMP-103, Boston, Mass.).

[1513] 9. Abl Peptide Substrate (Biotin-EAIYAAPFAKKK-amide) at 1 mM in50 mM Tris-HCL pH=8.0. (Use at 1.0 μM).

[1514] Procedure

[1515] Reagents were first mixed according to the following regimen: ONEPLATE (ul) PER WELL (μl) 10X Kinase Buffer 1100 10 10 mM DTT 1100 10 10mM cold ATP 5.5 0.05  1 mM Abl Peptide 11 0.1 ³³P-γ-ATP at 10 μCi/μl 220.2 H₂O 5462 49.65

[1516] The above reaction mixture was dispensed into each well of aFlashplate at 70 μl/well. To test the effect of a compound on Abl kinaseactivity, the test compound either in a fixed concentration or inserially diluted concentrations in 100% DMSO was added to appropriatewells at 1 μl/well.

[1517] Enzyme Abl was diluted in enzyme dilution buffer as following:Enzyme Dilution Buffer 3289 μl Abl enzyme (100 Units/μl)  11 μl

[1518] The kinase reaction was started by adding 30 μl of diluted Ablenzyme solution to each well on the Flashplate containing hot ATP (2μCi/well) and Abl peptide substrate (at 1 μM final conc.), except wellsof column 12 rows E and F, which were used to calculate the platebackground. The Flashplate was swirled to mix and was incubated at 30°C. for 60 minutes. Then, the reaction mixture was discarded and theFlashplate was washed 3 times each with 200 μL Wash/Stop Buffer.Subsequently, each well on the Flashplate was filled with 200 μl ofWash/Stop buffer. The amount of ³³P retained in each well was measuredusing a Packard TopCount after the plate was sealed with a transparentplate sealer.

[1519] When a test compound inhibited c-Abl kinase activity, the wellcontaining such the test compound contained less ³³P as compared to thewell without the compound. Tested under the described assay conditions,compounds within the scope of the invention demonstrated inhibitoryeffect on c-Abl kinase.

[1520] In order to test the potency of inhibition of present compounds,an IC₅₀ for an individual compound was measured using the aboveprocedure. As used herein, the IC₅₀ for c-Abl kinase activity refers tothe concentration of an inhibitor at which the activity of c-Abl kinaseis reduced by one-half as compared with reactions containing noinhibitor. The IC₅₀ for c-Abl kinase activity of individualrepresentative compounds of the present invention are listed in Table B.TABLE B IC50 of compounds for the c-Abl kinase activity IC50 CompoundNumber (uM) 2 0.011 8 0.694 11 0.118 12 0.020 13 0.173 14 0.038 22 0.01926 0.134 29 0.005 30 0.491 32 0.002 36 0.064 38 0.002 39 0.013 41 0.07844 0.007 54 0.971 63 0.419 90 10.290 97 0.227 116 0.386 118 0.427 1190.524 122 1.260 124 1.850 128 0.313 129 10.780 129 2.360 130 0.236 1320.665 133 0.498 134 1.160 140 1.410 156 0.089 157 0.371 160 1.020 1700.075 172 0.084 179 0.870 180 0.082 181 0.056 182 0.093 185 0.666 1881.400 190 0.069 199 0.027 200 0.020 201 0.217 202 2.650 203 0.160 2040.165 205 0.328 207 0.062 208 0.009 209 0.007 218 0.439 226 0.245 2270.641 247 0.033 249 0.035 253 0.03795 256 0.055 260 0.013 261 0.064 2620.027 263 0.512 265 0.085 266 0.015 267 0.326 268 0.020 269 0.101 2700.036 280 0.363 281 1.580 282 0.043 283 0.340 284 0.069 286 2.950 2873.450 289 2.400 292 0.001 299 0.198 309 0.822 310 1.471 330 0.091 3343.300 337 2.742 339 2.180 341 0.350 348 0.011 358 0.338 359 0.143 3600.077 361 0.043 363 0.001 369 0.047 370 0.006 371 0.905 373 0.010 3740.051 376 0.060 379 0.014 380 0.327 381 1.496 382 0.019 383 0.183 3840.004 385 0.012 386 0.020 388 0.046 389 0.017 390 0.000 391 0.014 3960.002 398 0.010 400 0.005 401 0.014 415 0.219 419 0.292 420 0.335 4223.078 432 0.096 448 0.003 449 0.023 457 0.004 459 0.070 460 0.004 4610.337 462 0.000 463 0.008 465 0.051 466 0.191 467 0.244 468 0.603 4690.027 490 0.038 595 0.460

[1521] 3. Anti-Cell Proliferation Assays

[1522] In addition to the above cell-free assays, the biologicalactivities of the compounds of the invention were also measured incell-based assays. One such assay is to measure the effect of thecompound on cell proliferation in the presence or absence of PDGFstimulation in various cell types.

[1523] 3a. Anti-Cell Proliferation in Normal Cells in the Presence ofPDGF Stimulation

[1524] The effect of compounds of the invention on cell proliferation innormal human primary cells, in particular, cryopreserved human coronaryartery smooth muscle cells (HCASMC), in the presence of PDGF stimulationwas tested based on incorporation of ¹⁴C-thymidine into DNA of cells.

[1525] Materials

[1526] The following materials were purchased from their respectivesources: Recombinant human PDGF beta homodimer, rhPDGF-BB (herein afterreferred as “PDGF-BB”) purchased from R&D System (Minneapolis, Minn.,Cat. No 220-BB); Cryopreserved human coronary artery smooth muscle cells(HCASMC), tissue culture medium for HCASMC, and smooth muscle growthsupplement (SMGS) purchased from Cascade Biologics (Portland, Oreg.,HCASMC Cat. No: C-017-5C; Medium 231 Cat. No: M-231-500; and SMGS Cat.No: S-007-25); 96-well CytoStar tissue culture treated scintillatingmicroplates purchased from Amersham (Piscataway, N.J., Cat. No:RPNQO160); Methyl ¹⁴C-thymidine at 56 mCi/mmol (250 μCi/2.5 mL)purchased from NEN (Cat. No.: NEC568); DMSO from Sigma (St. Louis, Mo.,Cat. No: D-5879); Sterile reagent reservoirs from Costar (VWRInternational, Inc., West Chester, Pa., Cat. No: 4870); Dulbecco's PBSfrom Gibco (Cat. No: 14190-136); Backing tape white plate cover forbottom of CytoStar plate from Packard (Cat. No: 6005199)

[1527] Procedure

[1528] HCASMC were seeded at approx. 4000 cells/well in a volume of 100μl of complete Medium 231 with SMGS. Cells were grown for 48 hrs untilthey reach 80% confluence. They were then quiesced in SMGS-free Medium231 for 24 hrs. Cell media were replenished with SMGS-free Medium 231containing PDGF-BB at 50 ng/mL in a total volume of 100 μl/well; and 1μl of test compounds in serially diluted concentrations in 100% DMSO wasadded to each well. For the maximum growth control wells, only 1 μl of100% DMSO was added; for minimum growth (blank) wells, 1 μl of 10 mMcycloheximide was added to each well. After 24 hours incubation, 20 μlof ¹⁴C-thymidine mix was added to each well and the ¹⁴C-thymidine mixwas made according the following regimen: Reagent: One Plate (μl) Onewell (μl) ¹⁴C-thymidine 220 2 SMGS-free Medium 231 1980 18 Total Mix2200 20

[1529] Cells were incubated for an additional 24 hrs in media containingtest compounds, PDGF-BB and ¹⁴C-thymidine. Then, the reaction mixturewas discarded and the plate was washed 3 times each with 200 μl PBS.Subsequently, each well on the plate was filled with 200 μl of PBS. Thetop of the plate was sealed with transparent plate sealer and whiteplate backing sealers were applied to the bottom of plates. The retained¹⁴C inside each well was measured using a Packard TopCount.

[1530] The amount of ¹⁴C retained in a well correlates to theproliferation of cells inside the well. When a test compound inhibitedPDGF-BB induced HCASMC proliferation, the well containing such acompound retained less ¹⁴C as compared to the maximum growth controlwells without the compound. In order to test the potency of inhibitionof the present compound, IC₅₀ of an individual compound on theinhibition of PDGF-BB induced HCASMC proliferation was measured usingthe above procedure. As used herein, said IC₅₀ refers to theconcentration of the test compound at which the amount of PDGF-BBinduced HCASMC proliferation is reduced by one-half as compared to themaximum growth control wells without the compound. Table C showsexamples of the IC₅₀ for representative compounds of the invention.

[1531] 3b. Anti-Cell Proliferation in Normal Cells in the Absence ofPDGF Stimulation

[1532] The effect of compounds of the invention on cell proliferation innormal human primary cell, in particular, human umbilical veinendothelial cells (HUVEC), in the absence of PDGF stimulation was testedbased on incorporation of BrdU into DNA of cells.

[1533] Materials:

[1534] The following materials were purchased from their respectivesources: HUVEC cells from Cascade Biologics, Cat No: C-015-10C; Medium200 from Cascade Biologics, Cat No: M-200-500; Low serum growthsupplements (LSGS) from Cascade Biologics, Cat No: S-003-10; F12-Kmedium from Gibco/BRL, Cat No: 21127-022; BrdU kit from Roche, Cat No: 1647 229; and Trypsin/EDTA solution from Cascade Biologics, Cat No:R-001-100.

[1535] Procedure

[1536] For propigation, HUVEC cells were grown in M-200 mediumsupplemented with LSGS. For studies, cells were detached withTrypsin/EDTA solution and washed three times with 10 mL of F12K (LS, lowserum) medium and then centrifuged at 400×G for 5 minutes. F-12K (LS)medium is F-12K medium containing 0.2% heat-treated fetal bovine serum.

[1537] Cell concentration was adjusted to about 5×10⁴ cells/mL in F-12K(LS) medium, and 200 μl (approx. 1×10⁴ cells) were added to each well ofa 96-well plate. Cells were then incubated for 16 to 20 hours at 37° C.under 95% air/5% CO₂ to allow the cells to attach and become quiescent.

[1538] Cell proliferation was stimulated by adding 50 μL of a 1:10dilution of LSGS in F12K (LS). Maximum-stimulated control wells wereprepared by adding 50 μl of a 1:10 dilution of LSGS. Zero control wellscontained 50 SL of F-12K (LS) medium only. Test compounds in 100% DMSOwere added at a volume of 2.5 μl to achieve the desired final drugconcentration. Replicates of eight wells per condition were tested.Cells were incubated at 37° C. overnight. On the next day 25 μL of BrdU(1:100 dilution of stock in F-12K (LS) medium) was added to each well.

[1539] Cells were incubated for an additional 20-24 hours. The mediumwas removed and the cells were fixed by adding 200 μL of FixDentsolution (included in the BrdU kit) to each well and then incubated atroom temperature for an additional 30 minutes. FixDent was removed byflicking and blotting the plates, and 100 μL of anti-BrdU-POD (includedin the BrdU kit) diluted at a 1:100 dilution in antibody dilutionsolution (included in the BrdU kit) was added to each well. The dilutedanti-BrdU-POD solution was prepared shortly before use. The plates wereincubated at room temperature for 90 minutes.

[1540] The unbound antibody was removed by washing three times with WashSolution (200 uL per wash). Wash Solution was prepared by making a 1:10dilution of Wash Buffer Stock (included in the BrdU kit) with distilledwater. Substrate solution (included in the BrdU kit) (100 uL) was addedto each well and incubated for an additional 30-40 minutes. Plates werethen read at 405 nm on a 96-well plate reader.

[1541] In order to test the potency of inhibition of the presentcompound, IC₅₀ of an individual compound on the inhibition of PDGF-BBindependent HUVEC proliferation was measured using the above procedure.As used herein, said IC₅₀ refers to the concentration of the testcompound at which the amount of HUVEC proliferation is reduced byone-half as compared to the maximum growth control wells without thecompound. Table C shows examples of the IC₅₀ for representativecompounds of the invention.

[1542] 3c. Anti-Cell Proliferation in Tumor Cells

[1543] The effect of compounds of the invention on cell proliferation invarious tumor cells was tested based on incorporation of ¹⁴C-thymidineinto DNA of cells.

[1544] Materials

[1545] Similar to those described above in 3a, except that differentcells, cell growth medium, and growth supplements were used. Human tumorcell lines derived from various human tissue origins (LoVo from colon,H460 from lung, T47D from breast, PC3 from prostate, A375 from melanoma,AsPC1 from pancreas) were obtained from the American Type CultureCollection (ATCC) and cultured under specified conditions required foreach cell type, as provided by ATCC. Complete medium was obtained fromCellgro: Iscove's medium with 10% Fetal Bovine Serium (FBS) (Mediatech,Inc., Herndon, Va. 20171, Cat. No. 10-016-CV).

[1546] Procedure

[1547] Tumor cells were seeded at approx. 3000-8000 cells per well in avolume of 100 μl of complete medium. Cells were grown for 24 hours incomplete medium, and 1 μl of test compound was serially diluted in 100%DMSO and added to each well. For maximum growth control wells, only 1 μlof 100% DMSO was added. After 24 hours incubation, 20 μl of¹⁴C-thymidine master mix was added to each well and the ¹⁴C-thymidinemaster mix was pepared according to the following regimen: Reagent: OnePlate (μl) One well (μl) ¹⁴C-thymidine 220 2 Complete medium 1980 18Total Mix 2200 20

[1548] Cells were incubated for an additional 24 hours at 37° C. inmedium containing test compound and ¹⁴C-thymidine. Then, the reactionmixture was discarded and the plate was washed 2 times each with 200 μlPBS. Subsequently, each well on the plate was filled with 200 μl of PBS.The top of the plate was sealed with transparent plate sealer and whiteplate backing sealers were applied to the bottom of plates. The retained¹⁴C inside each well was measured using a Packard TopCount.

[1549] In order to test the potency of inhibition of the presentcompound, IC₅₀ of an individual compound on the inhibition of tumor cellline proliferation was measured using the above procedure. As usedherein, said IC₅₀ refers to the concentration of the test compound atwhich the amount of tumor cell proliferation is reduced by one-half ascompared to the maximum growth control wells without the compound. TableC shows examples of the IC₅₀ for representative compounds of theinvention. TABLE C IC₅₀ of representative compounds on cellproliferation HCASMC HUVEC Cpd (PDGF-BB) (LSGS) H460 LoVo PC3 T47D A375AsPC1 No. (μM) (μM) (μM) (μM) (μM) (μM) (μM) (μM) 4 0.268 1.730 0.0300.012 0.048 0.030 1.580 0.427 11 0.014 0.002 0.033 0.002 0.014 0.0070.005 0.03 12 0.106 0.031 0.003 0.011 0.013 0.031 0.011 0.077 14 0.0034.870 0.010 0.011 0.02 0.032 0.007 0.592 22 0.278 2.150 9.270 13.45049.500 0.381 11.550 >10 30 0.002 >1.0 0.290 0.423 0.175 8.200 0.507 >1039 0.009 0.015 9.950 10.530 >10 >10 >50 >10 63 0.014 2.460 3.67 2.4 6.122.6 2.84 10.3 91 0.071 0.004 97 0.019 1.910 0.424 0.225 1.68 0.622 0.3625.67 122 0.125 0.223 14.300 3.840 6.340 10.500 14.400 >10 157 0.0080.218 3.590 2.140 3.130 1.900 1.230 >10 330 0.049 1.200 3.700 0.3030.355 2.176 1.550 388 0.006 0.018 0.004 0.003 0.002 0.155 432 0.0350.012 0.006 0.002 0.040 420 4.100 3.800 0.276 0.822 0.214 4.300

[1550] 3d. Anti-Cell Proliferation in Leukemia Cells

[1551] The effect of compounds of the invention on cell proliferation inleukemia cells, in particular, the human chronic myelogenous leukemia(CML) K562 cell line, was tested using flow cytometry and trypan blueexclusion cell counting assays. The CML K562 cell line has been found toexpress the oncogene bcr/abl, the genetic hallmark of human CML (Wu etal., 1995, Leukemia, 9(5):58-862).

[1552] Material and Procedure

[1553] The human chronic myelogenous leukemia (CML) K562 cell line wasobtained from American Type Culture Collection (ATCC) and cultured underspecified conditions, as provided by ATCC. A Becton DickinsonFACSCalibur instrument was used for flow cytometry analyses. A CycleTESTPLUS DNA Reagent Kit (Cat. No. 340242, Becton Dickinson) was used in thestudy for cell staining. The standard operating procedure and a protocolfor CycleTEST PLUS DNA Reagent Kit from Becton Dickinson have beenfollowed to carry out the study. Briefly, flow cytometric analysis ofthe differentially stained CML K562 cell line was used to estimate theDNA content and cell cycle phase distribution of cells treated withvarious concentrations of the compound for 24 hours. CML K562 cellstreated with compound No.14 were first stained with propidium iodidefollowed by fluorescence analysis to quantitate the cell cycle profile.Data analysis was carried out using the ModFit LT cell cycle dataanalysis program (Verity Software House, Topsham, Me. 04086,www.vsh.com). Cell viability test was performed using a Trypan Blueexclusion assay (Trypan Blue from Sigma, Cat No. T 0776) followingprocedures known to those skilled in the art.

[1554] Flow cytometry spectra demonstrated that after 24 hours oftreatment the compound caused accumulation of cells in the G2/M phase ofthe cycle and growth arrest of human CML K562 cells in aconcentration-dependent fashion (Table D). TABLE D Percent of cells atvarious growth phases after compound treatment Compound Conc. (nM) G0-G1(%) S phase (%) G2/M (%) 0 37 45 18 1 35 53 11 10 31 41 28 100 2 0 981000 3 4 93 10 000 5 5 90

[1555] Cell viability studies using the trypan blue exclusion assaydemonstrated that treating the K562 cells with compound No. 14 for 24hours caused a concentration-dependent decrease of cell proliferation inK562 cells. The IC50 for compound No.14 on K562 (i.e., the concentrationof the compound at which the amount of K562 cell proliferation isreduced by one—half as compared to the maximum growth control withoutthe compound) was about 10 nM as measured from the trypan blue exclusionassay.

[1556] Using similar protocols in flowcytometry and trypan blueexclusion cell counting assays, it was found that compound No. 14 alsoblocked growth of other cell types such as H460 and LoVo in the G2/Mcell cycle phase.

[1557] Any compound within the scope of the invention could be testedfor their ability to inhibit cell proliferation using various protocolsdescribed herein.

[1558] 4. Anti-Angiogenesis Assay.

[1559] Angiogenesis inhibitory activity of a compound of this inventioncan be measured in vivo using the matrigel mouse model (MM Assay) ofangiogenesis (Passaniti et al., Laboratory Investigation, 67: 519-528,1992). The matrigel mouse assay is a well-established method to quantifyangiogenesis (see e g. Capogrossi et al., Methods in Molecular Medicine,Vascular Disease: Molecular Biology and Gene Therapy Protocols, Editedby: A. H. Baker, Humana Press Inc., Totowa, N.J., 1999). The model hasbeen characterized extensively for its relevance as a mimic of theprocess of angiogenesis and has been used extensively to evaluate invivo both potential angiogenic and anti-angiogenic activity of numerouscompounds/agents. Compounds with demonstrated anti-angiogenic activityin other angiogenesis models (eg. RAR assay) have been shown to bepotent inhibitors of angiogenesis in the MM assay and produce tumorgrowth reduction in human tumor xenograft models. All proceduresinvolving animals were conducted in an animal facility fully accreditedby the American Association for Assessment and Accreditation ofLaboratory Animal Care (AAALAC) and in accordance with The Guide for theCare and Use of Laboratory Animals (NIH). Protocols were approved by theRWJ-PRI Internal Animal Care and Use Committee (IACUC).

[1560] Procedure

[1561] Normal male mice (C57BL/6J) were injected subcutaneously(ventrally below rib cage at abdominal midline) with 1.0 mL of chilledmatrigel supplemented with a single purified pro-angiogenic growthfactor (100-500 ng/mL of either rhPDGF-BB (supra), recombinant humanbasic fibroblast growth factor, rhFGF-basic (R&D System Cat. No 233-FB)or recombinant human vascular endothelial growth factor, rhVEGF (PanVeraCat. No R2951) and heparin (35 U/mL). Compounds are formulated as 0.1%suspensions (1 mg/mL final concentration) in 0.5% methylcellulose.Vehicle or test compounds (8-10 mice per treatment group) wereadministered orally by gavage beginning two hours after matrigelinjections. Dosing continued for three consecutive days (ie. qd dosingon day 1, bid dosing on day 2, and bid dosing on day 3). Approximately18 hours after the last dose of vehicle or drug, mice were euthanizedand the matrigel plugs were surgically removed intact (overlying skinremoved and plug cut out retaining some of the peritoneal lining forsupport). The plug was placed in pre-labeled tubes containing 1.0 mLdistilled water, minced and extracted for hemoglobin (Hb) overnight in a37° C. water bath with light shaking. The tubes were centrifuged thenext day at 3000 rpm for 20 minutes. Supernatants were removed and thehemoglobin concentration in the plug extract was measuredspectrophotometrically using the Drabkin's assay method (Drabkin'sreagent kit 525-A; SIGMA) and read on a Beckman DU 7400Spectrophotometer. Hemoglobin content of the plug was used as anindirect index of the angiogenic response and a reduction of plughemoglobin content was indicative of in vivo anti-angiogenic activity.The ability of compounds to inhibit PDGF-BB-stimulated angiogenesis invivo was compared directly to vehicle-treated control mice. Groupdifferences were analyzed statistically using the Mann-Whitney Test,with a p-value of 0.05 or less considered statistically significant.

[1562] Any compound within the scope of the invention can be testedusing the in vivo MM assay protocol described herein. Results forrepresentative compounds of the invention from the in vivo MM assaysupplemented with PDGF are shown in Table E. TABLE E RepresentativeCompounds Inhibit Angiogenesis in in vivo MM Assay supplemented withPDGF-BB. Compound No. % Inhibition @ 30 mg/kg po 14 40 12 45 26 42

[1563] 5. Anti-Tumor Assay

[1564] The anti-tumor activity of experimental compounds was evaluatedin vivo using the human tumor nude mouse xenograft model. All proceduresinvolving animals were conducted in an animal facility fully accreditedby the American Association for Assessment and Accreditation ofLaboratory Animal Care (AAALAC) and in accordance with The Guide for theCare and Use of Laboratory Animals (NIH). Protocols were approved by theRWJ-PRI Internal Animal Care and Use Committee (IACUC).

[1565] Human tumor cell lines (LoVo, MDA-MB-231, H460 etc.) wereobtained from American Type Culture Collection and cultured underspecified conditions required for each cell type. Female athymic nudemice (Charles River nu/nu) were injected subcutaneously in the inguinalregion of the thigh with 1-2×10⁶ tumor cells in 0.1 mL volume on dayzero. For growth delay studies, mice were dosed orally with vehicle(control group) or experimental drugs beginning three days after tumorcell inoculation. Compounds were prepared in 0.5% methylcellulose andtreatments were administered bid for 30-35 consecutive days. Tumorgrowth was measured twice a week using calipers for the duration of thetreatment. Tumor areas (mm²) were calculated as a product oflength×width. Body weights were obtained twice a week and loss of bodyweight was used as a measure of gross toxicity. At study termination,mice were euthanized and solid tumors were surgically excised intact andweighed. Final tumor weight served as the primary efficacy endpoint.Differences between treated and control mice were analyzed statisticallyby ANOVA and Dunnett's t-test.

[1566] Any compound within the scope of the invention can be tested invivo using the human tumor nude mouse xenograft model described herein.A representative compound, compound No.14, inhibited tumor growth by 72%with 50 mg/kg of the drug from the in vivo human tumor nude mousexenograft model study.

[1567] 6. Treatment in Combination with Irradiation

[1568] Radiotherapy is a major therapeutic modality in treating manytypes of cancers including human prostate and ovarian cancers. Theanti-proliferative activity of compounds within the scope of theinvention was tested in combination with irradiation treatment. Aclonogenicity assay was performed on two different human cancer celllines, DU145 (prostate cancer) and MDAH2774 (ovarian cancer) after thecombined treatment of irradiation and a representative compound of theinvention, compound No.14.

[1569] Materials:

[1570] Cells DU145 (prostate cancer) and MDAH2774 (ovarian cancer) wereobtained from ATCC; growth media MEM medium (Mediatech, Herndon, Va.)was supplemented with 8% FBS, 5 U/ml penicillin and 50 μg/mlStreptomycin (Hyclone, Logan, Utah), 2 mM L-glutamine (Hyclone, Logan,Utah), 25 mM HEPES (Hyclone, Logan, Utah); McCoy's 5A medium (Mediatech,Herndon, Va.) was supplemented with 8% FBS, 50 U/ml penicillin and 50μg/ml-Strep (Hyclone, Logan, Utah) and Glutamine 2 mM L-glutamine(Hyclone, Logan, Utah), ¹³⁷CS γ-source was a Gammacell 1000 Eliteirradiator (MDS Nordion, Kanata, Ontario, Canada); DMSO; 1× PBS;Methanol; 0.25% Crystal Violet, and 60 mm tissue culture dishes.

[1571] Procedure:

[1572] DU145 or MDAH2774 cells at desired cell number were plated inearly log phase on 60 mm dishes in MEM medium supplemented with 8% FBS,Penicillin, Streptomycin, L-glutamine, or McCoys medium supplementedwith 8% FBS, Penicillin, Streptomycin and Glutamine, respectively. Cellswere plated in triplicate. Compound No. 14 at various concentrations wasadded to the cells 14 h after the plating. The final concentrations ofthe compound in the cell media ranged from 1 to 100 nM. After 24 hincubation with the test compound plates were split in two groups ofequal size. The plates in the first group were irradiated with 7.3 Gy(plates containing DU145 cells) or 5.4 Gy (plates containing MDAH2774cells) using a ¹³⁷Cs γ-source (dose rate 3.32 Gy/min). The second groupof plates were treated identically but not irradiated. Cells wereincubated for an additional 24 hours in medium containing test compound.Then, the cells were replenished with fresh compound-free identicalmedium and allowed to grow for an additional 11 days. Cells were thenfixed with methanol, stained with 0.25% crystal violet, and the clonescontaining more than 50 cells were counted.

[1573] The results from these studies showed that starting at the 30 nMconcentration, compound No. 14 showed marked inhibitory activitiesagainst colony formation in both DU145 and MDAH2774 cells in thepresence or absence of radiation, but clearly the inhibitory effect wasgreater with radiation (Table F). The activity appeared to beconcentration-dependent with more dramatic effects achieved at 100 nMcompound with radiation in either cell line. The results are consistentwith the observation that compound No. 14 caused G2/M growth arrest inproliferating cancer cells, because cells under G2/M growth arrest areexpected to be more vulnerable and sensitive to additional insult, suchas radiation.

[1574] Any compound within the scope of the invention could be testedfor their ability to sensitize cells for radiation treatment using theprotocols described herein. TABLE F Clonogenicity assays on the combinedtreatment of irradiation and compound No. 14. No. of DU145 Clones No. ofMDAH2774 Clones (average of three plates) (average of three plates) W/ow/o Radiation w/Radiation Radiation w/Radiation (200 cells (1200 cells(200 cells (1000 cells Compound initially initially initially initiallyConc. (nM) plated) plated) plated) plated 0 133 134 101 121 1 118 117 98121 3 108 100 96 125 10 111 126 110 121 30 100 57 35 8 100 22 5 8 3

[1575] This study indicated that cancer cells that were pre-treated withlow concentrations of compound of the invention showed a greaterreduction of colony formation in combination with radiation, compared toeither compound or irradiation alone. These preliminary studies supportthe principal of using compound of the invention in combination withradiation therapy in cancers where radiotherapy is a standardtherapeutic modality.

[1576] 7. Conversion of Pro-Drugs to Parent Compounds

[1577] It has been demonstrated that the chemical modification of anactive agent can significantly change the chemical-physical propertiessuch as solubility, stability, absorption, transport andbio-availability in terms of a particular biospace (see BioreversibleCarrier in Drug Design, by Edward B. Roche, Pergamon Press, 1987).Prodrugs are molecules that can be reversibly hydrolyzed back to theactive agent by enzymes such as esterases. Pro-drugs of compounds withinthe scope of the invention were evaluated in in vitro and in vivo assaysystems for their possible in vivo conversion to parent compounds.

[1578] Various pro-drugs of a representative compound of the invention,compound No. 14, were incubated in freshly prepared rat plasma for 2hours. The PDGF-R kinase inhibitory activities of these pro-drugs wereassayed prior to and after the plasma incubation. The PDGF-R kinaseinhibition assay was performed as described supra. It was shown that 2 hincubation in plasma increased the PDGF-R kinase inhibitory activity ofthe pro-drugs significantly. This suggests that a significant amount ofpro-drug had been converted to the parent drug in rat plasma. Indeed, asignificant amount of parent compound had been detected by HPLC analysesfollowing the 2 h incubation with rat plasma (Table G).

[1579] Furthermore, pro-drugs have been administered orally to rats (10mg/kg) in pharmacokinetics studies, and the conversion of pro-drugs tothe parent compound was montitored by HPLC/MS/MS analyses. Parentcompound or the glucuronide conjugates of the parent compound wasdetected in the rat plasma from the pharmacokinetics studies (Table G).TABLE G conversion of representative pro-drugs to parent compound No. 14measured by HPLC. Incubation in Fast PK (0.5 h) (conc. μM) rat plasma (2h) Glucuronide Compound No. % of Parent Prodrug Parent conjugates 578  0% 7.8 0 0.007 432  22% 0.08 0.05 0.9 465   6% 0.223 0 6.664 433  47%0.06 0.1 3.9 471  56% 0 1.856 34.79 436 1.5% 0.038 0 3.347

[1580] The conversion of pro-drugs to any parent compound within thescope of the invention could be tested using the protocols describedherein.

[1581] Methods of Use of the Compounds of the Invention

[1582] Compounds of the invention can be used in methods oftreatment/prevention for cell proliferation disorders or a disorderrelated to PDGF-R. They can also be used in methods of identifying newPDGF-R inhibitors, for example via rational design.

[1583] 1. Methods of Identifying Novel PDGF-R Kinase Inhibitors Based onRational Design.

[1584] In one aspect of this invention, compounds of the invention canbe used to identify novel PDGF-R kinase inhibitors based on rationaldesign.

[1585] As used herein, “rational design” refers to the process ofdesigning a PDGF-R kinase inhibitor based on the three-dimensionalstructure of an inhibitor of PDGF-R kinase, preferably the methodinvolving the three-dimensional structure of an inhibitor of PDGF-Rkinase complexed with a PDGF-R protein, preferably a human PDGF-Rprotein, and more preferably a kinase catalytic domain of human PDGF-Rprotein. As used herein, “PDGF-R kinase catalytic domain” refers to apolypeptide consisting of a minimal amino acid sequence required forPDGF-R kinase activity, wherein the minimal amino acid sequence requiredfor PDGF-R kinase activity can be readily determined by those skilled inthe art. The catalytic domain can be that of a PDGF-R from human or ananimal. For example, the “PDGF-R kinase catalytic domain” can compriseamino acid 545 to 1106 of GenBank Access NO: AAA36427.

[1586] Structure based rational design has been used successfully foridentifying novel small molecule inhibitors for a variety of enzymes,such as proteases and protein tyrosine phosphatases. A method foridentifying novel PDGF-R kinase inhibitors based on rational designcomprises the steps of: (a) determining a three-dimensional structure ofthe compound of Fomula I or II in the absence or presence of apolypeptide comprising the PDGF-R kinase catalytic domain; (b) analyzingthe three-dimensional structure for the compound alone or for theintermolecular interaction between said compound and PDGF-R; (c)selecting a compound that mimics the structure for the compound alone orincorporates the predictive interaction; (d) synthesizing said designedcompound; and (e) determining the ability of the molecule to bind andinhibit PDGF-R kinase activity. These steps can be repeated to obtainthe optimal compounds by fine tuning the interaction features.

[1587] The three-dimensional structure can be obtained by, for example,X-ray crystallography, nuclear magnetic resonance, or homology modeling,all of which are well-known methods.

[1588] A particular method of the invention comprises analyzing thethree-dimensional structure for the intermolecular interaction betweensaid compound and PDGF-R, preferably the active kinase domain of PDGF-R.The present invention encompasses the use of information of thethree-dimensional structure of the compound of Fomula (I) or (II)complexed with PDGF-R in molecular modeling software systems to assistin analyzing intermolecular interactions. The likely binding site onPDGF-R as well as the key residues on the compound of Formula (I) or(II), which are critical for the intermolecular interaction, will beidentified and analyzed.

[1589] Another particular method of the invention comprises designing acompound that incorporates the predictive interaction identified above.Such computer-assisted modeling and drug design may utilize informationsuch as chemical conformational analysis, electrostatic potential of themolecules, protein folding, etc. Therefore, depending on theintermolecular interaction between the compound of Formula (I) or (II)and PDGF-R, novel PDGF-R kinase inhibitors will be designed to allow thespecific binding of the designed compound to PDGF-R. The compound ofFormula (I) or (II) may serve as a template for the initial design.

[1590] Another particular method of the invention comprises synthesizingthe designed compounds that incorporate the predictive interactionidentified above. Such a class of compounds can be synthesized using avariety of methods known in the art. For example, the synthesis methodsdescribed herein or the modification of these methods may prove to beuseful to synthesize the designed compounds.

[1591] Yet another particular method of the invention comprises assayingthe new compounds for their ability to bind and inhibit PDGF-R activity.The ability of a compound to inhibit PDGF-R kinase activity can bemeasured using any of the biological assays described supra, includingthe cell-free PDGF-R kinase assay; the PDGF-BB stimulated HCASMC cellproliferation and the human tumor cell proliferation assay; the in vivoanti-angiogenesis MM assay; and the human tumor mouse xenograft assay.

[1592] Because compounds within the scope of the invention alsoexhibited inhibitory activity for the c-Abl kinase, novel c-Abl kinaseinhibitors can be identified by rational design using procedure similarto that described herein.

[1593] Such a method comprises the steps of:

[1594] (a) determining a three-dimensional structure of the compound ofFomula I or II in the absence or presence of a polypeptide comprisingthe c-Abl kinase catalytic domain;

[1595] (b) analyzing the three-dimensional structure for the compoundalone or for the intermolecular interaction between said compound andc-Abl;

[1596] (c) selecting a compound that mimics the structure for thecompound alone or incorporates the predictive interaction;

[1597] (d) synthesizing said designed compound; and

[1598] (e) determining the ability of the molecule to bind and inhibitc-Abl kinase activity.

[1599] 2. Methods of Treatment/Prevention

[1600] In another aspect of this invention, compounds of the inventioncan be used to inhibit or reduce PDGF-R kinase or c-Abl kinase activityin a cell or a subject, or to treat disorders related to PDGF-R or cellproliferation in a subject.

[1601] In one embodiment to this aspect, the present invention providesa method for reducing or inhibiting the kinase activity of PDGF-R orc-Abl in a cell comprising the step of contacting the cell with acompound of Formula (l) or (II). The present invention also provides amethod of inhibiting the kinase activity of PDGF-R or c-Abl in a subjectcomprising the step of administering a compound of Formula (I) or (II)to the subject. The present invention further provides a method ofinhibiting cell proliferation in a cell comprising the step ofcontacting the cell with a compound of Formula (I) or (II).

[1602] The kinase activity of PDGF-R or c-Abl in a cell or a subject canbe determined by procedures well known in the art, such as the PDGF-Rkinase assay or the c-Abl kinase assay described supra.

[1603] The term “subject” as used herein, refers to an animal,preferably a mammal, most preferably a human, who has been the object oftreatment, observation or experiment.

[1604] In other embodiments to this aspect, the present inventionprovides both prophylactic and therapeutic methods for treating asubject at risk of (or susceptible to) developing a cell proliferativedisorder or a disorder related to PDGF-R.

[1605] In one example, the invention provides methods for preventing ina subject a cell proliferative disorder or a disorder related to PDGF-R,by administering to the subject prophylactically effective amount of apharmaceutical composition comprising the compound of Formula (I) or(II) and a pharmaceutically acceptable carrier. Administration of saidprophylactic agent can occur prior to the manifestation of symptomscharacteristic of the cell proliferative disorder or disorder related toPDGF-R, such that a disease or disorder is prevented or, alternatively,delayed in its progression.

[1606] In another example, the invention pertains to methods of treatingin a subject a cell proliferative disorder or a disorder related toPDGF-R by administering to the subject therapeutically effective amountof a pharmaceutical composition comprising the compound of Formula (I)or (II) and a pharmaceutically acceptable carrier. Administration ofsaid therapeutic agent can occur concurrently with the manifestation ofsymptoms characteristic of the disorder, such that said therapeuticagent serves as a therapy to compensate for the cell proliferativedisorder or disorders related to PDGF-R.

[1607] The term “prophylactically effective amount” refers to an amountof an active compound or pharmaceutical agent that inhibits or delays ina subject the onset of a disorder as being sought by a researcher,veterinarian, medical doctor or other clinician.

[1608] The term “therapeutically effective amount” as used herein,refers to an amount of active compound or pharmaceutical agent thatelicits the biological or medicinal response in a subject that is beingsought by a researcher, veterinarian, medical doctor or other clinician,which includes alleviation of the symptoms of the disease or disorderbeing treated.

[1609] Methods are known in the art for determining therapeutically andprophylactically effective doses for the instant pharmaceuticalcomposition.

[1610] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

[1611] As used herein, the terms “disorders related to PDGF-R”, or“disorders related to PDGF receptor”, or “disorders related to PDGFreceptor tyrosine kinase” shall include diseases associated with orimplicating PDGF-R activity, for example, the overactivity of PDGF-R,and conditions that accompany with these diseases. The term“overactivity of PDGF-R” refers to either 1) PDGF-R expression in cellswhich normally do not express PDGF-R; 2) PDGF expression by cells whichnormally do not express PDGF; 3) increased PDGF-R expression leading tounwanted cell proliferation; 4) increased PDGF expression leading tounwanted cell proliferation; or 5) mutations leading to constitutiveactivation of PDGF-R. Examples of “disorders related to PDGF-R” includedisorders resulting from over stimulation of PDGF-R due to abnormallyhigh amount of PDGF or mutations in PDGF, or disorders resulting fromabnormally high amount of PDGF-R activity due to abnormally high amountof PDGF-R or mutations in PDGF-R. It is known that overactivity of PDGFhas been implicated in the pathogenesis of a number of serious diseases,including cancers (glioma, lung, breast, colorectal, prostate, gastricand esophageal, leukemias and lymphomas), and other cell proliferativedisorders, such as atherosclerosis, transplantation-inducedvasculopathies, neointima formation, lung fibrosis, restenosis,pulmonary fibrosis, glomerulonephritis, glomerulosclerosis, congenitalmulticystic renal dysplasia, kidney fibrosis, and rheumatoid arthritis(Ostman A, Heldin C H., Adv. Cancer Res, 80:1-38, 2001, and referencestherein).

[1612] The term “cell proliferative disorders” refers to unwanted cellproliferation of one or more subset of cells in a multicellular organismresulting in harm (i.e., discomfort or decreased life expectancy) to themulticellular organisms. Cell proliferative disorders can occur indifferent types of animals and humans. For example, as used herein “cellproliferative disorders” include neoplastic and other cell proliferativedisorders. As used herein, a “neoplastic disorder” refers to a tumorresulting from uncontrolled cellular overgrowth. Examples of neoplasticdisorders include but are not limited to cancers such as, gliomacancers, lung cancers, breast cancers, colorectal cancers, prostatecancers, gastric cancers, esophageal cancers, colon cancers, pancreaticcancers, ovarian cancers, myelodysplasia, multiple myeloma, leukemiasand lymphomas. Examples of leukemias include, but are not limited tochronic myelogenous leukemia (CML); acute lymphocytic leukemia (ALL);chronic neutrophilic leukemia (CNL); acute undifferentiated leukemia(AUL); and acute myelogenous leukemia (AML). Examples of other cellproliferative disorders, include but are not limited to,atherosclerosis, transplantation-induced vasculopathies, neointimaformation, lung fibrosis, macular degeneration, restenosis, pulmonaryfibrosis, glomerulonephritis, glomerulosclerosis, congenital multicysticrenal dysplasia, kidney fibrosis, diabetic retinopathy and rheumatoidarthritis.

[1613] In a further embodiment to this aspect, the invention encompassesa combination therapy for treating or inhibiting the onset of a cellproliferative disorder or a disorder related to PDGF-R in a subject. Thecombination therapy comprises administering to the subject atherapeutically or prophylactically effective amount of the compound ofFormulae (I) or (II), and one or more other anti-cell proliferationtherapy including chemotherapy, radiation therapy, gene therapy andimmunotherapy.

[1614] In an embodiment of the present invention, the compound of thepresent invention may be administered in combination with chemotherapy.As used herein, chemotherapy refers to a therapy involving achemotherapeutic agent. A variety of chemotherapeutic agents may be usedin the combined treatment methods disclosed herein. Chemotherapeuticagents contemplated as exemplary including, but not limited to,adriamycin, dactinomycin, mitomycin, carminomycin, daunomycin,doxorubicin, tamoxifen, taxol, taxotere, vincristine, vinblastine,vinorelbine, etoposide (VP-16), 5-fluorouracil (5FU), cytosinearabinoside, cyclophohphamide, thiotepa, methotrexate, camptothecin,herceptin, actinomycin-D, mitomycin C, cisplatin (CDDP), aminopterin,combretastatin(s) and derivatives and prodrugs thereof.

[1615] In another embodiment of the present invention, the compound ofthe present invention may be administered in combination with radiationtherapy. As used herein, “radiation therapy” refers to a therapy thatcomprises exposing the subject in need thereof to radiation. Suchtherapy is known to those skilled in the art. The appropriate scheme ofradiation therapy will be similar to those already employed in clinicaltherapies wherein the radiation therapy is used alone or in combinationwith other chemotherapeutics.

[1616] In another embodiment of the present invention, the compound ofthe present invention may be administered in combination with a genetherapy. As used herein, “gene therapy” refers to a therapy targeting onparticular genes involved in tumor development. Possible gene therapystrategies include the restoration of defective cancer-inhibitory genes,cell transduction or transfection with antisense DNA corresponding togenes coding for growth factors and their receptors, or with theso-called ‘suicide genes’.

[1617] In other embodiments of this invention, the compound of thepresent invention may be administered in combination with animmunotherapy. As used herein, “immunotherapy” refers to a therapytargeting particular protein involved in tumor development viaantibodies specific to such protein. For example, monoclonal antibodiesagainst vascular endothelial growth factor have been used in treatingcancers.

[1618] Where a second pharmaceutical is used in addition to the compoundof the invention, the two pharmaceuticals may be administered togetherin a single composition, separately, sequentially, at approximately thesame time, or on separate dosing schedules.

[1619] As will be understood by those of ordinary skill in the art, theappropriate doses of chemotherapeutic agents will be generally similarto or less than those already employed in clinical therapies wherein thechemotherapeutics are administered alone or in combination with otherchemotherapeutics. By way of example only, agents such as cisplatin, andother DNA alkylating agents are used widely to treat cancer. Theefficacious doses of cisplatin used in clinical applications is of 20mg/m² for 5 days every three weeks for a total of three courses.Cisplatin is not absorbed orally and must therefore be delivered viainjection intravenously, subcutaneously, intratumorally orintraperitoneally. Further useful agents include compounds thatinterfere with DNA replication, mitosis and chromosomal segregation.Such chemotherapeutic compounds including adriamycin, also known asdoxorubicin, etoposide, verapamil, podophyllotoxin, and the like, arewidely used in a clinical setting for the treatment of neoplasms. Thesecompounds are administered through bolus injections intravenously atdoses ranging from 25-75 mg/m² at 21 day intervals for adriamycin, to35-50 mg/m²for etoposide intravenously or double the intravenous doseorally. Agents that disrupt the synthesis and fidelity of polynucleotideprecursors such as 5-fluorouracil (5-FU) are preferentially used totarget neoplastic cells. Although quite toxic, 5-FU is commonly used viaintravenous administration with doses ranging from 3 to 15 mg/kg/day.

[1620] The compound of the invention can be administered to a subjectsystemically, for example, intravenously, orally, subcutaneously,intramuscular, intradermal, or parenterally. The compound of theinvention can also be administered to a subject locally. Non-limitingexamples of local delivery systems include the use of intraluminalmedical devices that include intravascular drug delivery catheters,wires, pharmacological stents and endoluminal paving. The compound ofthe invention can further be administered to a subject in combinationwith a targeting agent to achieve high local concentration of thecompound at the target site. In addition, the compound may be formulatedfor fast-release or slow-release with the objective of maintaining thedrugs or agents in contact with target tissues for a period ranging fromhours to weeks.

[1621] The present invention also provides a pharmaceutical compositioncomprising the compound of Formula (I) or (II), or an optical isomer,enantiomer, diastereomer, racemate or pharmaceutically acceptable saltthereof, in association with a pharmaceutically acceptable carrier. Thepharmaceutical composition may contain between about 0.1 mg and 1000 mg,preferably about 100 to 500 mg, of the compound, and may be constitutedinto any form suitable for the mode of administration selected. Thephrases “pharmaceutically acceptable” refer to molecular entities andcompositions that do not produce an adverse, allergic or other untowardreaction when administered to an animal, or a human, as appropriate.Veterinary uses are equally included within the invention and“pharmaceutically acceptable” formulations include formulations for bothclinical and/or veterinary use. Carriers include necessary and inertpharmaceutical excipients, including, but not limited to, binders,suspending agents, lubricants, flavorants, sweeteners, preservatives,dyes, and coatings. Compositions suitable for oral administrationinclude solid forms, such as pills, tablets, caplets, capsules (eachincluding immediate release, timed release and sustained releaseformulations), granules, and powders, and liquid forms, such assolutions, syrups, elixirs, emulsions, and suspensions. Forms useful forparenteral administration include sterile solutions, emulsions andsuspensions.

[1622] The pharmaceutical composition of the present invention alsoincludes a pharmaceutical composition for slow release of the compoundof the invention. The composition includes a slow release carrier(typically, a polymeric carrier) and a compound of the invention. Slowrelease biodegradable carriers are well known in the art. These arematerials that may form particles that capture therein an activecompound(s) and slowly degrade/dissolve under a suitable environment(e.g., aqueous, acidic, basic, etc) and thereby degrade/dissolve in bodyfluids and release the active compound(s) therein. The particles arepreferably nanoparticles (i.e., in the range of about 1 to 500 nm indiameter, preferably about 50-200 nm in diameter, and most preferablyabout 100 nm in diameter).

[1623] The present invention also provides methods to prepare thepharmaceutical compositions of this invention. Compound of Formulae (I)or (II) or an optical isomer, enantiomer, ester, diastereomer, racemateor racemic mixture thereof, and salt thereof, as the active ingredient,is intimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending on the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, though other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Inpreparation for slow release, a slow release carrier, typically apolymeric carrier, and a compound of the invention are first dissolvedor dispersed in an organic solvent. The obtained organic solution isthen added into an aqueous solution to obtain an oil-in-water-typeemulsion. Preferably, the aqueous solution includes surface-activeagent(s). Subsequently, the organic solvent is evaporated from theoil-in-water-type emulsion to obtain a colloidal suspension of particlescontaining the slow release carrier and the compound of the invention.

[1624] The pharmaceutical compositions herein will contain, per dosageunit, e.g., tablet, capsule, powder, injection, teaspoonful and thelike, an amount of the active ingredient necessary to deliver aneffective dose as described above. The pharmaceutical compositionsherein will contain, per unit dosage unit, e.g., tablet, capsule,powder, injection, suppository, teaspoonful and the like, from about0.01 mg to 200 mg/kg of body weight per day. Preferably, the range isfrom about 0.03 to about 100 mg/kg of body weight per day, mostpreferably, from about 0.05 to about 10 mg/kg of body weight per day.The compounds may be administered on a regimen of 1 to 5 times per day.The dosages, however, may be varied depending upon the requirement ofthe patients, the severity of the condition being treated and thecompound being employed. The use of either daily administration orpost-periodic dosing may be employed.

[1625] Preferably these compositions are in unit dosage forms such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, auto-injector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofthe active ingredient of the present invention. The tablets or pills ofthe novel composition can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the lafter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterial can be used for such enteric layers or coatings, such materialsincluding a number of polymeric acids with such materials as shellac,acetyl alcohol and cellulose acetate.

[1626] The liquid forms in which the compound of Formulae (I) or (II)may be incorporated for administration orally or by injection include,aqueous solutions, suitably flavored syrups, aqueous or oil suspensions,and flavored emulsions with edible oils such as cottonseed oil, sesameoil, coconut oil or peanut oil, as well as elixirs and similarpharmaceutical vehicles. Suitable dispersing or suspending agents foraqueous suspensions, include synthetic and natural gums such astragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin. The liquid forms insuitably flavored suspending or dispersing agents may also include thesynthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

[1627] Advantageously, compounds of Formulae (I) or (II) may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three or four times daily.Furthermore, compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal skin patches well known to those of ordinary skill in thatart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

[1628] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

[1629] The daily dosage of the products may be varied over a wide rangefrom 1 to 5000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 and 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. An effectiveamount of the drug is ordinarily supplied at a dosage level of fromabout 0.01 mg/kg to about 200 mg/kg of body weight per day.Particularly, the range is from about 0.03 to about 15 mg/kg of bodyweight per day, and more particularly, from about 0.05 to about 10 mg/kgof body weight per day. The compounds may be administered on a regimenup to four or more times per day, preferably of 1 to 2 times per day.

[1630] Optimal dosages to be administered may be readily determined bythose skilled in the art, and will vary with the particular compoundused, the mode of administration, the strength of the preparation, themode of administration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

[1631] The compound of the present invention can also be administered inthe form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of lipids, including but notlimited to amphipathic lipids such as phosphatidylcholines,sphingomyelins, phosphatidylethanolamines, phophatidylcholines,cardiolipins, phosphatidylserines, phosphatidylglycerols, phosphatidicacids, phosphatidylinositols, diacyl trimethylammonium propanes, diacyldimethylammonium propanes, and stearylamine, neutral lipids such astriglycerides, and combinations thereof. They may either containcholesterol or may be cholesterol-free.

[1632] The compound of the present invention can also be administeredlocally. Any delivery device, such as intravascular drug deliverycatheters, wires, pharmacological stents and endoluminal paving, may beutilized. It is preferred that the delivery device comprises a stentthat includes a coating or sheath which elutes or releases thecompounds. The delivery system for such a device may comprise a localinfusion catheter that delivers the compound at a rate controlled by theadministor.

[1633] The present invention provides a drug delivery device comprisingan intraluminal medical device, preferably a stent, and a therapeuticdosage of a compound of the invention.

[1634] The term “stent” refers to any device capable of being deliveredby a catheter. A stent is routinely used to prevent vascular closure dueto physical anomalies such as unwanted inward growth of vascular tissuedue to surgical trauma. It often has a tubular, expanding lattice-typestructure appropriate to be left inside the lumen of a duct to relievean obstruction. The stent has a lumen wall-contacting surface and alumen-exposed surface. The lumen-wall contacting surface is the outsidesurface of the tube and the lumen-exposed surface is the inner surfaceof the tube. The stent can be polymeric, metallic or polymeric andmetallic, and it can optionally be biodegradable.

[1635] Commonly, stents are inserted into the lumen in a non-expandedform and are then expanded autonomously, or with the aid of a seconddevice in situ. A typical method of expansion occurs through the use ofa catheter-mounted angioplastry balloon which is inflated within thestenosed vessel or body passageway in order to shear and disrupt theobstructions associated with the wall components of the vessel and toobtain an enlarged lumen. Self-expanding stents as described in US2002/0016625 A1 (Falotico et al., in pending) may also be utilized. Thecombination of a stent with drugs, agents or compounds which preventinflammation and proliferation, may provide the most efficacioustreatment for post-angioplastry restenosis.

[1636] Compounds of the invention can be incorporated into or affixed tothe stent in a number of ways and in utilizing any number ofbiocompatible materials. In one exemplary embodiment, the compound isdirectly incorporated into a polymeric matrix, such as the polymerpolypyrrole, and subsequently coated onto the outer surface of thestent. Essentially, the compound elutes from the matrix by diffusionthrough the polymer molecules. Stents and methods for coating drugs onstents are discussed in detail in WIPO publication WO9632907. In anotherexemplary embodiment, the stent is first coated with as a base layercomprising a solution of the compound, ethylene-co-vinylacetate, andpolybutylmethacrylate. Then, the stent is further coated with an outerlayer comprising only polybutylmethacrylate. The outlayer acts as adiffusion barrier to prevent the compound from eluting too quickly andentering the surrounding tissues. The thickness of the outer layer ortopcoat determines the rate at which the compound elutes from thematrix. Stents and methods for coating are discussed in detail in U.S.Publication No. 2002/0016625 and references disclosed therein.

[1637] The solution of the compound of the invention and thebiocompatible materials/polymers may be incorporated into or onto astent in a number of ways. For example, the solution may be sprayed ontothe stent or the stent may be dipped into the solution. In a preferredembodiment, the solution is sprayed onto the stent and then allowed todry. In another exemplary embodiment, the solution may be electricallycharged to one polarity and the stent electrically changed to theopposite polarity. In this manner, the solution and stent will beattracted to one another. In using this type of spraying process, wastemay be reduced and more control over the thickness of the coat may beachieved. Compound is preferably only affixed to the outer surface ofthe stent which makes contact with one tissue. However, for somecompounds, the entire stent may be coated. The combination of the doseof compound applied to the stent and the polymer coating that controlsthe release of the drug is important in the effectiveness of the drug.The compound preferably remains on the stent for at least three days upto approximately six months and more, preferably between seven andthirty days.

[1638] Any number of non-erodible biocompatible polymers may be utilizedin conjunction with the compound of the invention. It is important tonote that different polymers may be utilized for different stents. Forexample, the above-described ethylene-co-vinylacetate andpolybutylmethacrylate matrix works well with stainless steel stents.Other polymers may be utilized more effectively with stents formed fromother materials, including materials that exhibit superelasticproperties such as alloys of nickel and titanium.

[1639] The present invention further provides a method for the treatmentof disorders related to PDGF-R, particularly restenosis, intimalhyperplasia or inflammation, in blood vessel walls, which comprises thecontrolled delivery, by release from an intraluminal medical device,such as a stent, of a compound of the invention in therapeutic effectiveamounts.

[1640] Methods for introducing a stent into a lumen of a body are wellknown and the compound-coated stents of this invention are preferablyintroduced using a catheter. As will be appreciated by those of ordinaryskill in the art, methods will vary slightly based on the location ofstent implantation. For coronary stent implantation, the ballooncatheter bearing the stent is inserted into the coronary artery and thestent is positioned at the desired site. The balloon is inflated,expanding the stent. As the stent expands, the stent contacts the lumenwall. Once the stent is positioned, the balloon is deflated and removed.The stent remains in place with the lumen-contacting surface bearing thecompound directly contacting the lumen wall surface. Stent implantationmay be accompanied by anticoagulation therapy as needed.

[1641] Optimum conditions for delivery of the compounds for use in thestent of the invention may vary with the different local deliverysystems used, as well as the properties and concentrations of thecompounds used. Conditions that may be optimized include, for example,the concentrations of the compounds, the delivery volume, the deliveryrate, the depth of penetration of the vessel wall, the proximalinflation pressure, the amount and size of perforations and the fit ofthe drug delivery catheter balloon. Conditions may be optimized forinhibition of smooth muscle cell proliferation at the site of injurysuch that significant arterial blockage due to restenosis does notoccur, as measured, for example, by the proliferative ability of thesmooth muscle cells, or by changes in the vascular resistance or lumendiameter. Optimum conditions can be determined based on data from animalmodel studies using routine computational methods.

[1642] Another alternative method for administering compounds of thisinvention may be by conjugating the compound to a targeting agent whichdirects the conjugate to its intended site of action, i.e., to vascularendothelial cells, or to tumor cells. Both antibody and non-antibodytargeting agents may be used. Because of the specific interactionbetween the targeting agent and its corresponding binding partner, acompound of this invention can be administered with high localconcentrations at or near a target site and thus treats the disorder atthe target site more effectively.

[1643] The antibody targeting agents include antibodies orantigen-binding fragments thereof, that bind to a targetable oraccessible component of a tumor cell, tumor vasculature, or tumorstroma. The “targetable or accessible component” of a tumor cell, tumorvasculature or tumor stroma, is preferably a surface-expressed,surface-accessible or surface-localized component. The antibodytargeting agents also include antibodies or antigen-binding fragmentsthereof, that bind to an intracellular component that is released from anecrotic tumor cell. Preferably such antibodies are monoclonalantibodies, or antigen-binding fragments thereof, that bind to insolubleintracellular antigen(s) present in cells that may be induced to bepermeable, or in cell ghosts of substantially all neoplastic and normalcells, but are not present or accessible on the exterior of normalliving cells of a mammal.

[1644] As used herein, the term “antibody” is intended to refer broadlyto any immunologic binding agent such as IgG, IgM, IgA, IgE, F(ab′)2, aunivalent fragment such as Fab′, Fab, Dab, as well as engineeredantibodies such as recombinant antibodies, humanized antibodies,bispecific antibodies, and the like. The antibody can be either thepolyclonal or the monoclonal, although the monoclonal is preferred.There is a very broad array of antibodies known in the art that haveimmunological specificity for the cell surface of virtually any solidtumor type (see a Summary Table on monoclonal antibodies for solidtumors in U.S. Pat. No. 5,855,866 to Thorpe et al). Methods are known tothose skilled in the art to produce and isolate antibodies against tumor(see i.e., U.S. Pat. No. 5,855,866 to Thorpe et al., and U.S. Pat. No.6,342,219 to Thorpe et al.).

[1645] The non-antibody targeting agents includes growth factors, suchas PDGF, VEGF and FGF; peptides containing the tripeptide R-G-D, thatbind specifically to the tumor vasculature; and other targetingcomponents such as annexins and related ligands. In addition, a varietyof other organic molecules can also be used as targeting agents fortumors, examples are hyaluronan oligosaccharides which specificallyrecognize Hyaluronan-binding protein, a cell surface protein expressedduring tumor cell and endothelial cell migration and duringcapillary-like tubule formation (U.S. Pat. No. 5,902,795, Toole et al.),and polyanionic compounds, particularly polysulphated or polysulphonatedcompounds such as N- and O-sulfated polyanionic polysaccharides,polystyrene sulfonate and other polyanionic compounds described in U.S.Pat. No. 5,762,918 (Thorpe), which selectively bind to vascularendothelial cells.

[1646] Techniques for conjugating therapeutic moiety to antibodies arewell known, see, e.g., Amon et al., “Monoclonal Antibodies ForImmunotargeting Of Drugs In Cancer Therapy”, in Monoclonal AntibodiesAnd Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss,Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, inControlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53(Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of CytotoxicAgents In Cancer Therapy: A Review”, in Monoclonal Antibodies '84:Biological And Clinical Applications, Pinchera et al. (eds.), pp.475-506 (1985). Similar techniques can also be applied to attachcompounds of the invention to non-antibody targeting agents. Thoseskilled in the art will know, or be able to determine, methods offorming conjugates with non-antibody targeting agents, such as smallmolecules, oligopeptides, polysaccharides, or other polyanioniccompounds.

[1647] Although any linking moiety that is reasonably stable in blood,can be used to link the compound of the invention to the targetingagent, biologically-releasable bonds and/or selectively cleavablespacers or linkers is preferred. “Biologically-releasable bonds” and“selectively cleavable spacers or linkers” still have reasonablestability in the circulation, but are releasable, cleavable orhydrolyzable only or preferentially under certain conditions, i.e.,within a certain environment, or in contact with a particular agent.Such bonds include, for example, disulfide and trisulfide bonds andacid-labile bonds, as described in U.S. Pat. Nos. 5,474,765 and5,762,918 and enzyme-sensitive bonds, including peptide bonds, esters,amides, phosphodiesters and glycosides as described in U.S. Pat. Nos.5,474,765 and 5,762,918. Such selective-release design featuresfacilitate sustained release of the compounds from the conjugates at theintended target site.

[1648] The present invention provides a pharmaceutical composition thatcomprises an effective amount of the compound of the inventionconjugated to a targeting agent and a pharmaceutically acceptablecarrier described supra.

[1649] The present invention further provides a method of treating of adisorder related to PDGF-R, particularly a tumor, which comprisesadministering to the subject a therapeutic effective amount of compoundof Formulae (I) or (II) conjugated to a targeting agent. When proteinssuch as antibodies or growth factors, or polysaccharides are used astargeting agents, they are preferably administered in the form ofinjectable compositions. The injectable antibody solution will beadministered into a vein, artery or into the spinal fluid over thecourse of from 2 minutes to about 45 minutes, preferably from 10 to 20minutes. In certain cases, intradermal and intracavitary administrationare advantageous for tumors restricted to areas close to particularregions of the skin and/or to particular body cavities. In addition,intrathecal administrations may be used for tumors located in the brain.

[1650] Therapeutically effective doses of the compound of the inventionconjugated to a targeting agent depend on the individual, the diseasetype, the disease state, the method of administration and other clinicalvariables. The effective dosages are readily determinable using datafrom an animal model. Experimental animals bearing solid tumors arefrequently used to optimize appropriate therapeutic doses prior totranslating to a clinical environment. Such models are known to be veryreliable in predicting effective anti-cancer strategies. For example,mice bearing solid tumors, are widely used in pre-clinical testing todetermine working ranges of therapeutic agents that give beneficialanti-tumor effects with minimal toxicity.

[1651] One skilled in the art will recognize that the compounds ofFormulae (I) or (II) may have one or more asymmetric carbon atoms intheir structure. It is intended that the present invention includeswithin its scope the stereochemically pure isomeric forms of thecompounds as well as their racemates. Stereochemically pure isomericforms may be obtained by the application of art known principles.Diastereoisomers may be separated by physical separation methods such asfractional crystallization and chromatographic techniques, andenantiomers may be separated from each other by the selectivecrystallization of the diastereomeric salts with optically active acidsor bases or by chiral chromatography. Pure stereoisomers may also beprepared synthetically from appropriate stereochemically pure startingmaterials, or by using stereoselective reactions.

[1652] Some of the compounds of the present invention may have trans andcis isomers. In addition, where the processes for the preparation of thecompounds according to the invention give rise to mixture ofstereoisomers, these isomers may be separated by conventional techniquessuch as preparative chromatography. The compounds may be prepared as asingle stereoisomer or in racemic form as a mixture of some possiblestereoisomers. The non-racemic forms may be obtained by either synthesisor resolution. The compounds may, for example, be resolved into theircomponent enantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation. The compounds may also beresolved by covalent linkage to a chiral auxiliary, followed bychromatographic separation and/or crystallographic separation, andremoval of the chiral auxiliary. Alternatively, the compounds may beresolved using chiral chromatography. The scope of the present inventionis intended to cover all such isomers or stereoisomers per se, as wellas mixtures of cis and trans isomers, mixtures of diastereomers andracemic mixtures of enantiomers (optical isomers) as well.

[1653] While the foregoing specification teaches the principles of thepresent invention, with examples provided for the purpose ofillustration, it will be understood that the practice of the inventionencompasses all of the usual variations, adaptations and/ormodifications as come within the scope of the following claims and theirequivalents.

What is claimed is:
 1. A compound of Formula (I):

wherein, n is an integer from 1 to 4; R¹ is selected from the groupconsisting of hydrogen, lower alkyl, —OH, alkoxy, -oxo, —NH₂, —NH(alkyl)and —N(alkyl)₂;

is selected from the group consisting of an aryl, a five to six memberedmonocyclic heteroaryl, a nine to ten membered benzo-fused heteroaryl, anine to ten membered benzo-fused heterocycloalkyl group, and a nine toten membered benzo-fused cycloalkyl group; wherein the benzo-fusedheteroaryl, benzo-fused heterocycloalkyl or benzo-fused cycloalkyl groupis attached to the molecule such that the phenyl ring is bound directlyto the

portion of the molecule; p is an integer from 0 to 2; R² is selectedfrom the group consisting of

and —X-A¹-Y-A²; wherein, X and Y are each independently absent orselected from the group consisting of —O—, —NH—, —N(alkyl)-, —S—, —SO—,—SO₂—, —OC(═O), —C(═O)O—, —NHC(═O)—, —N(alkyl)C(═O)—, —C(═O)NH—,—C(═O)N(alkyl)-, —OC(═O)O—, —NHC(═O)O—, —OC(═O)NH—, —N(alkyl)C(═O)O—,—OC(═O)N(alkyl)-, —NHC(═O)NH——NHC(═O)N(alkyl)-, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)N(alkyl)-, —NHSO₂—, —SO₂NH—, —N(alkyl)SO₂— and—SO₂N(alkyl)-; A¹ is absent or selected from alkyl or alkenyl; A² isselected from alkyl, alkenyl, or H; wherein, when A¹ orA² is alkyl oralkenyl, the alkyl or alkenyl group may be optionally substituted withone or more groups independently selected from halogen, cyano, hydroxy,alkoxy, thio, halogenated alkoxy, —OC(═O)alkyl, —OC(═O)Oalkyl, amino,alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, dialkylamino,—NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)NH₂,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂;

is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl; wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, is optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, amino, thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy,halogenated alkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, ordialkylamino, —NHC(═O)NH₂; —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂; q is an integer from 0 to 4; R³ is selected from thegroup consisting of halogen, hydroxy, amino, thio, nitro, cyano, alkyl,halogenated alkyl, alkoxy, halogenated alkyloxy, alkylamino,—NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, or dialkylamino, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —OC(═O)NHalkyl, —NHC(═O)Oalkyl,—N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl, —N(alkyl)SO₂alkyl, thioalkyl,halogenated thioalkyl, —SO₂alkyl, halogenated —SO₂alkyl,—NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ and —OC(═O)N(alkyl)₂;provided that the sum of p and q is an integer from 0 to 4; L¹ is absentor selected from the group consisting of alkyl;

is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl; or an optical isomer, enantiomer,diastereomer, racemate, or pharmaceutically acceptable salt thereof. 2.A compound as in claim 1 of the formula (Ia)


3. A compound as in claim 1 wherein n is an integer from 1 to 2; R¹ ishydrogen;

is selected from the group consisting of phenyl, a five to six memberedheteroaryl and a nine to ten membered benzo-fused heterocycloalkylgroup; wherein the nine to ten membered benzo-fused heterocycloalkylgroup is attached to the molecule such that the phenyl ring is bounddirectly to the

portion of the molecule; p is an integer from 0 to 2; R² is selectedfrom the group consisting of di(lower alkyl)amino-alkoxy, loweralkyl-alkoxy, hydroxy substituted alkoxy and

wherein A¹ is selected from the group consisting of lower alkyl; whereinthe lower alkyl is optionally substituted with one to two substituentsindependently selected from hydroxy, amino, alkylamino or dialkylamino;and wherein

is selected from the group consisting of a five or six memberedheteroaryl and a five or six membered heterocycloalkyl; wherein theheteroaryl or heterocycloalkyl is optionally substituted with one to twosubstituents independently selected from halogen, lower alkyl, loweralkoxy, amino, lower alkylamino or di(lower alkyl)amino; q is an integerfrom 0 to 2; R³ is selected from the group consisting of lower alkyl andlower alkoxy, and halogen; L¹ is absent or lower alkyl;

is selected from the group consisting of phenyl and a five or sixmembered heteroaryl group; wherein the phenyl or heteroaryl group isoptionally substituted with one to two substituents independentlyselected from halogen, lower alkyl, lower alkoxy or benzyloxy; or anoptical isomer, enantiomer, diastereomer, racemate or pharmaceuticallyacceptable salt thereof.
 4. A compound as in claim 1 wherein n is aninteger from 1 to 2; R¹ is hydrogen;

is selected from the group consisting of phenyl, thienyl and1,3-benzodioxolyl; p is an integer from 0 to 2; R² is selected from thegroup consisting of 3-dimethylamino-propoxy, 3-methoxy-propoxy,2,3-dihydroxy-n-propoxy, 3-hydroxy-propoxy,2-hydroxy-3-pyrrolidin-1-yl-propoxy and3-(4-methyl-piperazin-1-yl-propoxy; q is an integer from 0 to 2; R³ isselected from the group consisting of methyl, methoxy, ethoxy. L¹ isabsent or CH₂;

is selected from the group consisting of phenyl and pyridyl; wherein thephenyl is optionally substituted with one to two substituentsindependently selected from fluoro, chloro, methyl, methoxy orbenzyloxy; or an optical isomer, enantiomer, diastereomer, racemate orpharmaceutically acceptable salt thereof.
 5. A compound as in claim 1wherein

is selected from the group consisting of phenyl, a five memberedheteroaryl, a nine membered benzo-fused heteroaryl and a nine memberedbenzo-fused hetercycloalkyl; R¹ is selected from the group consisting ofhydrogen, hydroxy, oxo and lower alkyl; p is an integer from 0 to 2; R²is selected from the group consisting of heterocycloalkyl, benzyloxy,di(lower alkyl)amino-lower alkoxy, lower alkoxy-lower alkoxy,heteroaryl-lower alkoxy, heterocycloalkyl-lower alkoxy and lower alkoxy;wherein the heterocycloalkyl, whether alone or as part of a substituentgroup is optionally substituted with a substiuent selected from loweralkyl or hydroxy; wherein the lower alkoxy, whether alone or as part ofa subtituent group is optionally substituted with one to two hydroxy; qis an integer from 0 to 2; R³ is selected from the group consisting ofhydroxy, lower alkoxy, lower alkyl, halogen, amino, (lower alkyl)aminoand di(lower alkyl)amino; L¹ is absent or selected from the groupconsisting of lower alkyl;

is selected from the group consisting of phenyl, cycloalkyl, benzo-fusedcycloalkyl, heteroaryl and heterocycloalkyl; wherein the phenyl isoptionally substituted with one to three substituents independentlyselected from hydroxy, carboxy, halogen, lower alkyl, hydroxysubstituted lower alkyl, lower alkoxy, lower alkoxycarbonyl,trifluoromethyl, trifluoromethoxy, lower alkylamino, di(loweralkyl)amino, cyano, nitro, aminocarbonyl, lower alkylaminocarbonyl,di(lower alkyl)aminocarbonyl, (hydroxy substituted loweralkyl)-aminocarbonyl, (heteroaryl-lower alkyl)-aminocarbonyl, loweralkyl-thio, trifluoromethylthio, aralkyloxy, heterocycloalkyl, loweralkyl substituted heterocycloalkyl or heterocycloalkyl-sulfonyl; or anoptical isomer, enantiomer, diastereomer, racemate or pharmaceuticallyacceptable salt thereof.
 6. A compound as in claim 5, wherein

is selected from the group consisting of phenyl, thienyl and1,3-benzodioxolyl; R¹ is selected from the group consisting of hydrogen,hydroxy, oxo and methyl; p is an integer from 0 to 2; R² is selectedfrom the group consisting of piperidinyl, 4-methyl-piperizin-1-yl,3-(4-methyl-piperazin-1-yl)-propoxy, 3-dimethylamino-propoxy,3-methoxy-propoxy, 3-morpholin-1-yl-propoxy, 3-pyrrolidin-1yl-propoxy,3-imidazol-1-yl-propoxy, 2,3-dihydroxy-propoxy, 3-hydroxy-propoxy,2-hydroxy-3-pyrrolidin-1-yl-propoxy, and benzyloxy; q is an integer from0 to 2; R³ is selected from the group consisting of hydroxy, methoxy,ethoxy, isopropoxy, methyl, bromo, fluoro, chloro, amino anddimethylamino; L¹ is absent or selected from the group consisting ofmethyl and ethyl;

is selected from the group consisting of phenyl, 4-chlorophenyl,3-chlorophenyl, 2-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl,3-ethylphenyl, 2-isopropylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-methoxycarbonylphenyl, 3-ethoxycarbonylphenyl,4-ethoxycarbonylphenyl, 3-hydroxyphenyl, 3-cyanophenyl, 4-cyanophenyl,3-carboxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl,3-hydroxymethyl-phenyl, 3-(1-hydroxyethyl )phenyl, 3-methylthiophenyl,3-trifluoromethylthiophenyl, 3-benzyloxy-phenyl, 4-benzyloxyphenyl,4-methylaminophenyl, 4-dimethylaminophenyl, 3-aminocarbonylphenyl,2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dimethylphenyl,2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl,3,5-dimethoxyphenyl, 3,5-di(trifluoromethyl)-phenyl,3,5-di(tert-butyl)-phenyl, 3-chloro-4-fluoro-phenyl,3-chloro-4-methoxy-phenyl, 4-chloro-3-methyl-phenyl,5-chloro-2-methyl-phenyl, 5-chloro-2-methoxy-phenyl,4-bromo-2-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl,4-fluoro-3-nitro-phenyl, 3,4,5-trimethoxyphenyl,4-(4-methyl-piperidin-1-yl)-phenyl, 4-(piperidine-4-sulfonyl)-phenyl,3-(2-hydroxy-ethylaminocarbonyl)-phenyl,3-(3-pyrrolidn-1-yl-propylaminocarbonyl)-phenyl, cyclohexyl, 2-furyl,3-pyridyl, 4-morpholinyl, 5-indolyl, 6-indazolyl, 5-indanyl, piperidinyland 3,4-methylenedioxyphenyl; or an optical isomer, enantiomer,diastereomer, racemate or pharmaceutically acceptable salt thereof.
 7. Acompound of Formula (II):

wherein:

is selected from the group consisting of Formulae A-1, A-2 and A-3:

wherein Formula A-1 is attached on the b¹ side of Formula A-1 to the L²ring of formula (II) and optionally substituted with one substituentselected from the group consisting of Formulae A-1-a, A-1-b and A-1-c:

wherein Formula A-1-a is attached on the a¹ side to adjacent carbons onthe d¹ or d² side of Formula A-1;

wherein Formula A-1-b is attached on the a²side to adjacent carbons onthe d¹or d² side of Formula A-1; and

wherein Formula A-1-c is attached on the a⁶ side to adjacent carbons onthe d¹or d² side of Formula A-1; wherein R⁸ is H or alkyl;

wherein Formula A-2 is attached on the b² side of Formula A-2 to the L²ring of formula (II), and A¹, A², A³, A⁴ are (i) —N—; or (ii) —C—substituted with H or alkoxy, wherein the alkoxy may be optionallyfurther substituted with alkoxy on a terminal carbon or up to 3 halogenatoms on a terminal carbon; provided that at least one and no more thantwo of A¹, A², A³, A⁴ are —N—; and

wherein Formula A-3 is attached on the b³ side of Formula A-3 to the L²ring of formula (II), and B¹, B² and B³ are independently (i) —CH—optionally substituted with alkyl, aryl, alkoxy, or halogen, (ii) —S—;(iii) —O—; or (iv) —N—; provided that no more than one of B¹, B² or B³is —S-or —O—, and, provided that when one of B¹, B² or B³ is —S-or —O—,then the adjacent ring members are not —S-or —O—; R⁹ is independentlyselected from the group consisting of: alkoxy, alkyl, alkylamino, amino,cyano, dialkylamino, halogen, halogenated alkyl, halogenated alkyloxy,halogenated —SO₂alkyl, halogenated thioalkyl, hydroxy,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —SO₂alkyl, thioand thioalkyl; L² is a linking group selected from the group consistingof: —(CH₂)₁₋₄— —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;wherein R¹⁰⁰ is selected from: alkyl, hydroxy, aryl, alkoxy, oxo, —NH₂,—NH(alkyl)—N(alkyl)₂, ═N(OH) or —NH₂OH; provided that when L² is—CH₂CH₂—, neither R⁶ nor R⁷ is —CH₂—(C═O)NHalkyl, —CH₂—(C═O)N(alkyl)₂ or—CH₂C(═O)Oalkyl; provided that when L² is —OCH(R¹⁰⁰)—, R¹⁰⁰ is alkoxy,and

is phenyl, R⁵ is not —C(═O)NH—NH₂; and provided that when L² is —O— or—S—, neither R⁶ nor R⁷ is —CH₃; R¹⁰ is independently selected from thegroup consisting of

and —X¹-A²⁰-Y¹-A²¹; wherein X¹ and Y¹ are each independently absent orselected from the group consisting of: -(alkyl)C(═O)N(alkyl)—,—C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—,—N(alkyl)C(═O)NH—, —N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—,—NHC(═O)N(alkyl)-, —NHC(═O)NH, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O),—OC(═O)N(alkyl)-, —OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—,—SO₂N(alkyl)-, and —SO₂NH—; A²⁰ is absent or selected from alkyl oralkenyl; and A²¹ is selected from alkyl, alkenyl, or H; wherein when A²⁰or A²¹ is alkyl or alkenyl, the alkyl or alkenyl may be optionallysubstituted with one or more groups independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated —SO₂alkyl, halogenated thioalkyl, hydroxy,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl;

is selected from the group consisting of aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, nine to tenmembered benzo-fused cycloalkyl, and nine to ten membered benzo-fusedheterocycloalkyl; wherein, the aryl, cycloalkyl, partially unsaturatedcarbocycle, heteroaryl, heterocycloalkyl, benzo-fused cycloalkyl, orbenzo-fused heterocycloalkyl, are optionally substituted with one ormore substituents independently selected from halogen, hydroxy, amino,thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy, halogenatedalkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, or dialkylamino,—NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —OC(═O)NHalkyl,—NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl, —N(alkyl)SO₂alkyl,thioalkyl, halogenated thioalkyl, —SO₂alkyl, halogenated —SO₂alkyl,—NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or —OC(═O)N(alkyl)₂; s is aninteger from 0 to 2; m is an integer from 0 to 4; provided that when

is not substituted with Formulae A-1-a, A-1-b or A-1-c, the sum of m ands is an integer from 0 to 4, and when

is substituted with one of Formulae A-1-a, A-1-b, or A-1-c, the sum of mand s is an integer from 0 to 2; R⁶ and R⁷ are independently selectedfrom the group consisting of: (a) H; (b)

provided that R⁴ is not

—CH₂— substituted with one group selected from: —H, -methyl, —Oalkyl,—CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —(C═O)OH, —C(═O)Oalkyl, —C(═O)Oaryl,—C(═O)Oheteroaryl, —(C═O)NH₂, —(C═O)NHalkyl, —(C═O)N(alkyl)₂,—C(═O)alkyl, -phenyl-OCH₃ or -phenyl-OC(═O)alkyl; (d)—C(═O)(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, or benzyl; (e)—C(═O)CH₂O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, or benzyl;(f) —C(═O)alkyl, or —C(═O)(C₃₋₆)cycloalkyl, wherein said —C(═O)alkyl,and —C(═O)(C₃₋₆)cycloalkyl may be optionally substituted with one ormore groups independently selected from: —OH, —Oalkyl, —Oalkylaryl,—NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, or —OC(═O)alkyl; (g) —C(═O)(CH₂)₁₋₃aryl, —C(═O)aryl,—C(═O)(CH₂)₁₋₃heteroaryl, or —C(═O)heteroaryl, wherein said—C(═O)(CH₂)₁₋₃aryl, —C(═O)aryl, —C(═O)(CH₂)₁₋₃heteroaryl, and—C(═O)heteroaryl may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl; (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with methyl, ethyl,—OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, or heterocycloalkyl; (hh)—C(═O)alkylOC(═O)alkyl-terminating with —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, or heterocycloalkyl; (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminatingwith H, methyl, ethyl, or benzyl; (j) —C(═O)Oalkyl, or—C(═O)O(C₃₋₆)cycloalkyl, wherein said —C(═O)Oalkyl, and—C(═O)O(C₃₋₆)cycloalkyl may be optionally substituted with one or moregroups independently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, —OC(═O)alkyl,—C(═O)OH, —C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂;(k) —C(═O)O(CH₂)₁₋₃aryl, —C(═O)Oaryl, —C(═O)O(CH₂)₁₋₃heteroaryl, or—C(═O)Oheteroaryl, wherein said —C(═O)O(CH₂)₁₋₃aryl, —C(═O)Oaryl,—C(═O)O(CH₂)₁₋₃heteroaryl, or —C(═O)Oheteroaryl may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl; (l)—C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H, methyl, ethyl, benzyl,—CH₂CH₂NH₂, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl or —C(═O)alkyl; (m) —C(═O)NH₂,—C(═O)NH(C₁₋₂₀)alkyl, —C(═O)NH(C₃₋₆)cycloalkyl, or —C(═O)N(alkyl)₂,wherein said —C(═O)NH(C₁₋₂₀)alkyl, —C(═O)NH(C₃₋₆)cycloalkyl, and—C(═O)N(alkyl)₂ may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, —OC(═O)alkyl,—OC(═O)alkenyl, —NHC(═O)aryl, —C(═O)OH, —C(═O)O-alkyl, —C(═O)NH₂,—C(═O)NHalkyl, or —C(═O)N(alkyl)₂; and, wherein the aryl portion of said—NHC(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH, —O-alkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile; (n) —C(═O)NH(CH₂)₁₋₃aryl, —C(═O)NHaryl,—C(═O)NH(CH₂)₁₋₃heteroaryl, or —C(═O)NHheteroaryl, wherein said—C(═O)NH(CH₂)₁₋₃aryl, —C(═O)NHaryl, —C(═O)NH(CH₂)₁₋₃heteroaryl, and—C(═O)NHheteroaryl may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl; (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with H,methyl, ethyl, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃,—CH₂CH₂OC(═O)alkyl, or —C(═O)aryl; wherein the aryl portion of said—C(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH , —O-alkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile; (p) —C(═S)NH₂; (q) —C(═S)NHalkyl; (r)—C(═S)N(alkyl)₂; (s) —SO₂NH₂; (t) —SO₂NHalkyl; (u) —SO₂N(alkyl)₂; (v)—P(═O)(OCH₃)₂; and (w) —P(═O)(OCH₂CH₃)₂; provided that when R⁶ ispresent, R⁷ is absent; and provided that when R⁷ is present, R⁶ isabsent; R⁴ is selected from the group consisting of: H and

provided that if one of R⁶and R⁷ is

then R⁴ is H; L³ is absent or is a linking group selected from the groupconsisting of alkyldiyl, carbonyl or —SO₂—;

is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, aralkyl, a heteroaryl, aheterocycloalkyl, a nine to ten membered benzo-fused cycloalkyl, a nineto ten membered benzo-fused heteroaryl, and a nine to ten memberedbenzo-fused heterocycloalkyl; r is an integer from 0 to 4; and R⁵ isindependently selected from the group consisting of: alkyl, alkyl amino,alkyloxy, amino, —C(═O)NH₂, —C(═O)Oalkyl, —C(═O)OH, —CH₂OH, cyano,dialkylamino, halogen, halogenated alkyl, halogenated alkyloxy,halogenated SO₂-alkyl, halogenated thioalkyl, hydroxy, hydroxy alkyl,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —SO₂alkyl,—SO₂NH₂, thio, thioalkyl,

and —V—B¹⁰—W—B²⁰; wherein, V and W are each independently absent orselected from the group consisting of: —C(═O), —C(═O)N(alkyl)-,—C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—,—N(alkyl)C(═O)N(alkyl)-, —N(alkyl)C(═O)NH—, —N(alkyl)C(═O)O—,—N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-, —NHC(═O)NH—,—NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-, —OC(═O)NH—,—OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)- and —SO₂NH—; B¹⁰ is absent orselected from alkyl or alkenyl; B²⁰ is absent or selected from alkyl,alkenyl, or H; wherein, when B¹⁰ or B²⁰ is alkyl or alkenyl, the alkylor alkenyl group may be optionally substituted with one or more groupsindependently selected from: alkoxy, alkylamino, amino, cyano,dialkylamino, halogen, halogenated alkoxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl; and

is selected from the group consisting of: an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl, wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, is optionally substitutedwith one or more substituents independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated alkyl, halogenated —SO₂alkyl, halogenated thioalkyl,heteroaryl, hydroxy, hydroxy alkyl, —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —SO₂alkyl, thio or thioalkyl; or an optical isomer,enantiomer, diastereomer, racemate, or pharmaceutically acceptable saltthereof.
 8. A compound as in claim 7 wherein:

is selected from the group consisting of Formulae A-1, A-2 and A-3:

wherein Formula A-1 is attached on the b¹ side of Formula A-1 to the L²ring of formulae (II) and optionally substituted with one substituentselected from the group consisting of Formulae A-1-a, A-1-b and A-1-c:

wherein Formula A-1-a is attached on the a¹ side to adjacent carbons onthe d¹or d² side of Formula A-1;

wherein Formula A-1-b is attached on the a² side to adjacent carbons onthe d¹or d² side of Formula A-1; and

wherein Formula A-1-c is attached on the a⁶ side to adjacent carbons onthe d¹or d² side of Formula A-1; wherein R⁸ is H or lower alkyl;

wherein Formula A-2 is selected from the group consisting of pyridyl andpyrimidinyl; is attached on the b² side of Formula A-2 to the L² ring offormulae (II); and is optionally substituted on a carbon ring memberwith H or alkoxy, wherein the alkoxy may be optionally furthersubstituted with alkoxy on a terminal carbon or up to 3 halogen atoms ona terminal carbon; and

wherein Formula A-3 is selected from the group consisting of thienyl,isoxazolyl and furyl; is attached on the b³ side of Formula A-3 to theL² ring of formulae (II), and is optionally substituted on a carbon ringmember with C₁₋₄alkyl, aryl, alkoxy, or halogen.
 9. A compound as inclaim 7 wherein:

is:

wherein Formula A-4 is attached on the b¹ side of Formula A-4 to the L²ring of formula (II); and wherein m is an integer from 0 to 4; providedthat when

is Formula A-4, the sum of m and s is an integer from 0 to
 4. 10. Acompound as in claim 7 wherein: L² is a linking group selected from thegroup consisting of: —(CH₂)—, —(CH₂)₃₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—,—C(R¹⁰⁰)₂—, —O(CH₂)₁₋₄—, —OCH(R²⁰⁰)—, —OC(R¹⁰⁰)₂—, —NH—, —N(loweralkyl)-, —N(COalkyl)-, —N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-,—N(SO₂alkyl) and —N(SO₂aryl)-; wherein R²⁰⁰ is selected from: alkyl,hydroxy, aryl, oxo, —NH₂, —NH(alkyl) -N(alkyl)₂, ═N(OH) or —NH₂OH.
 11. Acompound as in claim 7 wherein: R⁹ and R¹⁰ are independently selectedfrom the group consisting of: 1-piperidinyl, 2-(pyrrolidin-1-yl)-ethoxy,2,3-dihydroxy-propoxy, 2-hydroxy-3-pyrrolidin-1-yl-propoxy,3-(4-methyl-piperazin-1-yl)-propoxy, 3-(N,N-dimethyl-amino)-propoxy,3-hydroxy-propoxy, 3-imidazol-1-yl-propoxy, 3-methoxy-propoxy,3-morpholin-4-yl-propoxy, 3-pyrrolidin-1-yl-2-hydroxy-propoxy,3-pyrrolidin-1-yl-propoxy, 4-methyl-piperazin-1-yl, amino, benzyl,benzyloxy, bromo, chloro, cyano, ethoxy, fluoro, H, hydroxy, isopropoxy,methoxy, methyl, N-(1-oxo-ethyl)-amino, and N,N-dimethyl-amino.
 12. Acompound as in claim 7 wherein: R⁶ and R⁷ are independently selectedfrom the group consisting of: (a) (b)

provided that R⁴ is not

(c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —C(═O)Oalkyl, —(C═O)NH₂,—C(═O)alkyl or -phenyl-OC(═O)alkyl; (f) —C(═O)alkyl optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —Oalkyl-phenyl or —OC(═O)alkyl; (g) —C(═O)phenyl optionallysubstituted with one or more groups independently selected from:—Oalkyl, chloro or fluoro,; (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with—OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, or pyrrolidinyl; (hh)—C(═O)alkylOC(═O)alkyl-terminating with —Oalkyl; (i)—C(═O)O(CH₂CH₂O—)₁₋₁₀ terminating with H or benzyl; (j)—C(═O)Oalkyloptionally substituted with one or more —Oalkyl groups; (k)—C(═O)Ophenyl optionally substituted with one or more chloro, fluorogroups; (l) —C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H; (m)—C(═O)NH(C₁₋₂₀)alkyl optionally substituted with one or more groupsindependently selected from: —NH₂, —NHalkyl, —N(alkyl)₂, pyrrolidinyl,morpholinyl, —NHC(═O)alkyl, —OC(═O)alkenyl, —NHC(═O)phenyl or—C(═O)Oalkyl; and, wherein the phenyl portion of said —NHC(═O)phenyl maybe optionally substituted with one or more groups independently selectedfrom: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, halogen andnitrile; (n) —C(═O)NHphenyl optionally substituted with one or morefluoro groups; (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with—CH₂CH₂OH and —C(═O)phenyl; wherein the phenyl portion of said—C(═O)phenyl may be optionally substituted with one or more —OHgroups;(p) —C(═S)NH₂; (u) —SO₂N(alkyl)₂; and (w) —P(═O)(OCH₂CH₃)₂; providedthat when R⁶ is present, R⁷ is absent; and provided that when R⁷ ispresent, R⁶ is absent.
 13. A compound as in claim 7 wherein: R⁶ and R⁷are independently selected from the group consisting of: H,

provided that R⁴ is not

1-methoxy-1-oxo-ethyl, 1-methyl-ethoxy-carbonyl, 1-oxo-butoxy-methyl,1-oxo-ethoxy-methyl, 1-oxo-ethyl, 1-oxo-propyl,2-(1-oxo-ethoxy)-1-oxo-ethyl, 2-(2-methoxy-1-oxo-ethoxy)-1-oxo-ethyl,2-(2-methyl-1-oxo-propoxy)-1-oxo-ethyl, 2-amino-2-oxo-ethyl,2,2-dimethyl-1-oxo-propoxy-methyl, 2-ethoxy2-oxo-ethyl,2-methoxy-2-oxo-ethyl, 2,6-difluoro-benzoyl,2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy-carbonyl,2-benzyloxy-1-oxo-ethyl, 2-benzyloxy-ethoxy-carbonyl,2-chloro-phenoxy-carbonyl, 2-fluoro-benzoyl, 2-hydroxy-1-oxo-ethyl,2-hydroxy-ethyl, 2-hydroxy-propyl, 2-methoxy-1-oxo-ethyl,2-methoxy-ethoxy-carbonyl, 2-methyl-1-oxo-propyl, 2-oxo-propyl,3-(N,N-diethyl amino)-1,3-dioxo-propyl,3-1H-pyrrolidin-1-yl-1,3-dioxo-propyl, 3-ethoxy-1,3-dioxo-propyl,3-1H-pyrrolidin-1-yl-1,3-dioxo-propyl, 4-(1-oxo-ethoxy)-benzyl,4-amino-1,4-dioxo-n-butyl, 4-ethoxy-1,4-dioxo-n-butyl,4-hydroxy-1,4-dioxo-n-butyl, 4-methoxy-1,4-dioxo-n-butyl,4-chloro-benzoyl, 4-chloro-phenoxy-carbonyl, 4-fluoro-benzoyl,4-fluoro-phenoxy-carbonyl, 4-methoxy-benzoyl,5-(N-methyl-amino)-1,5-dioxo-pentyl, 5-methoxy-1,5-dioxo-pentyl,benzoyl, diethoxy-phosphinyl, ethoxy-carbonyl, methoxy-carbonyl,methoxy-methyl, methyl, N-(2-ethoxy-2-oxo-ethyl)-amino-carbonyl,N-(2-1H-pyrrolidin-1-yl-ethyl)-amino-carbonyl,N-(2-amino-ethyl)-amino-carbonyl,N-(2-morpholin-4-yl-ethyl)-amino-carbonyl,N-(3-ethoxy-3-oxo-propyl)-amino-carbonyl,N-(3-fluoro-phenyl)-amino-carbonyl, N-(pentadecyl)-amino-carbonyl,N,N-dimethyl-amino-sulfonyl,N-[2-(2-methenyl-1-oxo-propoxy)-ethyl]-amino-carbonyl,N-[2-(3-methyl-1-methoxy-1-oxo)-n-butyl]-amino-carbonyl,N-[2-(4-methyl-1-methoxy-1-oxo)-pentyl]-amino-carbonyl,N-[2-(N,N-dimethyl-amino)-ethyl]-amino-carbonyl,N-[2-(N-benzoyl-amino)-ethyl]-amino-carbonyl,N-[2-(N-methyl-amino)-ethyl]-amino-carbonyl,N-[2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethyl]-amino-carbonyl,N-[2-[N-(1-oxo-ethyl)-amino]-ethyl]-amino-carbonyl,N-[2-[N-(2-hydroxy-benzoyl)-amino]-ethyl]-amino-carbonyl,N-[2-[N-(2-hydroxy-ethyl)-amino]-ethyl]-amino-carbonyl,N-[2-[N-(2-methyl-1-oxo-propyl)-amino]-ethyl]-amino-carbonyl,N-methyl-amino-carbonyl, N-methyl-amino-thiocarbonyl, andphenoxy-carbonyl, provided that when R⁶ is present, R⁷ is absent; andprovided that when R⁷ is present, R⁶ is absent.
 14. A compound as inclaim 7 wherein: L³ is absent or is a linking group selected from thegroup consisting of methylene, ethylene or carbonyl.
 15. A compound asin claim 7 wherein:

is selected from the group consisting of phenyl, cyclohexyl, furyl,imidazolyl, isoxazolyl, pyridyl, pyrimidinyl, indolyl, indazolyl,piperidinyl, morpholinyl, indanyl, 2,3-dihydro-1H-indolyl andbenzodioxolyl.
 16. A compound as in claim 7 wherein: R⁵ is independentlyselected from the group consisting of: methyl, ethyl, isopropyl,t-butyl, methoxy, ethoxy, —C(═O)NH₂, —C(═O)Omethyl, —C(═O)Oethyl,—C(═O)OH, cyano, dimethyl-amino, bromo, chloro, fluoro, trifluoromethyl,trifluoromethoxy, thio-trifluoromethyl, hydroxy, hydroxymethyl,hydroxyethyl, nitro, —SO₂NH₂, thiomethyl

and —V—B¹⁰—W—B²⁰.
 17. A compound as in claim 16 wherein: V and W areeach independently absent or selected from the group consisting of:—C(═O), —C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —NH—, —O— and —SO₂—; B¹⁰is absent or selected from methyl or ethyl,; wherein methyl or ethyl areoptionally substituted with one or more groups independently selectedfrom dimethyl-amino or hydroxy; and B²⁰ is absent or selected fromalkyl, alkenyl, or H, wherein, when B²⁰ is alkyl or alkenyl, the alkylor alkenyl group may be optionally substituted with one or more groupsindependently selected from: alkoxy, alkylamino, amino, dialkylamino,halogen, halogenated alkoxy, hydroxy, —NHC(═O)NH₂, —NHSO₂alkyl orthioalkyl.
 18. A compound as in claim 17 wherein:

is selected from the group consisting of phenyl, imidazolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyloptionally substituted with one or more substituents independentlyselected from methoxy, ethoxy, methyl, ethyl, bromo, chloro, fluoro,trifluoromethyl, pyridinyl, hydroxy or hydroxymethyl.
 19. A compound asin claim 9 wherein:

is selected from the group consisting of:1-(3-methoxy-phenyl)-(S*)ethyl; 2-(3-bromo)-pyridyl;2-(3-methyl)-pyridyl; 2-(3-methyl-5-bromo)-pyridyl;2-(4,6-dimethyl)-pyridyl; 2-(4-bromo)-pyridyl; 2-(piperidin-1-yl)-ethyl;2,2-difluoro-1,3-benzodioxol-4-yl; 2,3-dichloro-benzyl;2,3-dichloro-phenyl; 2,3-dihydro-1H-indol-1-yl; 2,3-dimethoxy-benzyl;2,4,6-trifluoro-phenyl; 2,4-dichloro-phenyl; 2,4-difluoro-benzyl;2,4-dimethoxy-phenyl; 2,4-dimethoxy-phenyl; 2,5-dichloro-benzyl;2,5-dichloro-phenyl; 2,5-difluoro-benzyl; 2,5-difluoro-phenyl;2,5-dimethoxy-benzyl; 2,5-dimethoxy-phenyl; 2,6-dichloro-benzyl;2,6-difluoro-benzyl; 2,6-difluoro-phenyl; 2-bromo-3-fluoro-phenyl;2-bromo-benzyl; 2-bromo-phenyl; 2-chloro-benzyl; 2-chloro-phenyl;2-ethyl-phenyl; 2-fluoro-benzyl; 2-fluoro-phenyl; 2-furyl;2-isopropyl-phenyl; 2-methoxy-benzyl; 2-methoxy-phenyl; 2-methyl-benzyl;2-methyl-phenyl; 2-morpholin-4-yl-ethyl; 2-pyridyl; 2-pyridyl-methyl;2-trifluoromethoxy-benzyl; 2-trifluoromethoxy-phenyl;2-trifluoromethyl-4-bromo-phenyl; 2-trifluoromethyl-benzyl;2-trifluoromethyl-phenyl; 3-(1-hydroxy-ethyl)-phenyl;3-(2,4-dimethoxy)-pyridyl; 3-(2-chloro)-pyridyl;3-(2-hydroxy-ethyl-amino-carbonyl)-phenyl; 3-(4-methoxy)-pyridyl;3-(4-methyl-piperazinyl-carbonyl)-phenyl; 3-(4-trifluoromethyl)-pyridyl;3-(amino-carbonyl)-phenyl; 3-(amino-sulfonyl)-phenyl;3-(ethoxy-carbonyl)-phenyl; 3-(methoxy-carbonyl)-phenyl;3-(trifluoromethyl-thio)-phenyl; 3,4,5-trimethoxy-phenyl;3,4-dichloro-benzyl; 3,4-dichloro-phenyl; 3,4-difluoro-benzyl;3,4-dimethoxy-phenyl; 3,4-dimethyl-benzyl; 3,4-methylenedioxy-phenyl;3,5-di(tert-butyl)-phenyl; 3,5-di(trifluoromethyl)-phenyl;3,5-dichloro-benzyl; 3,5-dichloro-phenyl; 3,5-difluoro-phenyl;3,5-dimethoxy-phenyl; 3,5-dimethyl-phenyl;3-[N-(3-pyrrolidin-1-yl-propyl)-amino-carbonyl]-phenyl;3-benzyloxy-phenyl; 3-bromo-phenyl; 3-carboxy-phenyl;3-chloro-4-fluoro-phenyl; 3-chloro-4-methoxy-phenyl;3-chloro-4-methyl-benzyl; 3-chloro-benzyl; 3-chloro-phenyl;3-cyano-phenyl; 3-ethoxy-phenyl; 3-ethyl-phenyl; 3-fluoro-benzyl;3-fluoro-phenyl; 3-hydroxymethyl-phenyl; 3-hydroxy-phenyl;3-isopropoxy-phenyl; 3-methoxy-5-trifluoromethyl-phenyl;3-methoxy-benzyl; 3-methyl-benzyl; 3-methyl-phenyl; 3-methylthio-phenyl;3-pyridyl; 3-pyridyl-methyl; 3-trifluoromethoxy-phenyl;3-trifluoromethyl-phenyl; 4-(4-methyl-piperazin-1-yl)-phenyl;4-(ethoxy-carbonyl)-phenyl; 4-(N,N-dimethyl-amino)-phenyl;4-(piperidin-4-yl-sulfonyl)-phenyl; 4-benzyloxy-phenyl; 4-bromo-phenyl;4-chloro-3-methyl-benzyl; 4-chloro-phenyl; 4-cyano-phenyl;4-dimethylamino-phenyl; 4-fluoro-3-chloro-phenyl;4-fluoro-3-nitro-phenyl; 4-fluoro-3-trifluoromethyl-phenyl;4-fluoro-benzyl; 4-fluoro-phenyl; 4-methoxy-benzyl;4-methyl-3-[N-[4-(3-pyridyl )-pyrimidin-2-yl]amino]-phenyl;4-methyl-benzyl; 4-methyl-phenyl; 4-trifluoromethoxy-phenyl;4-trifluoromethyl-phenyl; 5-(phenyl)-isoxazol-3-yl-methyl;5-bromo-2,3-dihydro-1H-indol-1-yl; 5-chloro-2-methoxy-phenyl;5-chloro-2-methyl-phenyl; 5-indanyl; 5-indolyl; 5-indolyl;5-trifluoromethyl-2-fluoro-phenyl; 6-indazolyl; benzyl; cyclohexyl;cyclohexyl-methyl; and phenyl.
 20. A compound of Formula (II-AA):

wherein: R¹⁰⁰ is selected from the group consisting of: H and alkyl;R^(B) and R^(C) are independently selected from the group consisting of:alkoxy; and R⁵ is selected from the group consisting of: alkoxy andhalogen; or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof.
 21. A compound as in claim 20,wherein R¹⁰⁰ is selected from the group consisting of: H, methyl, ethyl;R^(B) and R^(C) are independently selected from the group consisting of:methoxy and ethoxy; and R⁵ is selected from the group consisting of:methoxy, ethoxy, isopropoxy, chloro, bromo, and fluoro.
 22. A compoundof Formula (II-BB):

wherein R^(C) is —O(CH₂)₃OH; R¹⁰⁰ is selected from the group consistingof: H and alkyl; R^(B) is selected from the group consisting of: alkoxy;and R⁵ is selected from the group consisting of: alkoxy and halogen; oran optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof.
 23. A compound as in claim 22,wherein R¹⁰⁰ is selected from the group consisting of: H, methyl, ethyl;R^(B) is selected from the group consisting of: methoxy and ethoxy; andR⁵ is selected from the group consisting of: methoxy, ethoxy,isopropoxy, chloro, bromo, and fluoro.
 24. A comound of Formula (II-CC)

wherein R¹⁰⁰ is selected from the group consisting of: H and alkyl;R^(B) and R^(C) are independently selected from the group consisting of:alkoxy; and R⁵ is selected from the group consisting of: alkyl, cyano,hydroxy, alkoxy and halogen; or an optical isomer, enantiomer,diastereomer, racemate, or pharmaceutically acceptable salt thereof. 25.A compound as in claim 24 wherein R¹⁰⁰ is selected from the groupconsisting of: H, methyl, ethyl; R^(B) and R^(C) are independentlyselected from the group consisting of: methoxy and ethoxy; and R⁵ isselected from the group consisting of: methoxy, ethoxy, isopropoxy,chloro, methyl, cyano and hydroxy.
 26. A comound of Formula (II-DD)

wherein R^(C) is —O(CH₂)₃OH; R¹⁰⁰ is selected from the group consistingof: H and alkyl; R^(B) is selected from the group consisting of: alkoxy;and R⁵ is selected from the group consisting of: alkyl, cyano, hydroxy,alkoxy and halogen; or an optical isomer, enantiomer, diastereomer,racemate, or pharmaceutically acceptable salt thereof.
 27. A compound asin claim 16 wherein R¹⁰⁰ is selected from the group consisting of: H,methyl, and ethyl; R^(B) is selected from the group consisting of:methoxy and ethoxy; and R⁵ is selected from the group consisting of:methoxy, ethoxy, isopropoxy, chloro, methyl, cyano and hydroxy.
 28. Acomound of Formula (II-EE)

wherein R⁵ is selected from the group consisting of: alkoxy and halogen;and R^(C) is selected from the group consisting of: alkoxy,

or an optical isomer, enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof.
 29. A compound of Formula(II-FF)

wherein R⁹ is independently selected from the group consisting of:alkoxy, alkyl, alkylamino, amino, cyano, dialkylamino, halogen,halogenated alkyl, halogenated alkyloxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy, —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —SO₂alkyl, thio and thioalkyl; L² is a linking groupselected from the group consisting of: —(CH₂)₁₋₄—, —CH(R¹⁰⁰)—,—C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—, —OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—,—NH—, —N(lower alkyl)-, —N(COalkyl)-, —N(aryl)-, —N(CO₂alkyl)-,—N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-; wherein R¹⁰⁰ is selectedfrom: alkyl, hydroxy, aryl, alkoxy, oxo, —NH₂, —NH(alkyl) —N(alkyl)₂,═N(OH) or —NH₂OH; provided that when L² is —CH₂CH₂—, neither R⁶ nor R⁷is —CH₂—(C═O)NHalkyl, —CH₂—(C═O)N(alkyl)₂ or —CH₂C(═O)Oalkyl; providedthat when L² is —OCH(R¹⁰⁰)—, R¹⁰⁰ is alkoxy, and

is phenyl, R⁵is not —C(═O)NH—NH₂; and provided that when L² is —O— or—S—, neither R⁶ nor R⁷ is —CH₃; R¹⁰ is independently selected from thegroup consisting of

and X¹-A²⁰-Y¹-A²¹; wherein X¹ and Y¹ are each independently absent orselected from the group consisting of: -(alkyl)C(═O)N(alkyl)-,—C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—,—N(alkyl)C(═O)NH—, —N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—,—NHC(═O)N(alkyl)-, —NHC(═O)NH, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O),—OC(═O)N(alkyl)-, —OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—,—SO₂N(alkyl)-, and —SO₂NH—; A²⁰ is absent or selected from alkyl oralkenyl; and A²¹ is selected from alkyl, alkenyl, or H; wherein when A²⁰or A²¹ is alkyl or alkenyl, the alkyl or alkenyl may be optionallysubstituted with one or more groups independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated —SO₂alkyl, halogenated thioalkyl, hydroxy,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl;

is selected from the group consisting of aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, nine to tenmembered benzo-fused cycloalkyl, and nine to ten membered benzo-fusedheterocycloalkyl; wherein, the aryl, cycloalkyl, partially unsaturatedcarbocycle, heteroaryl, heterocycloalkyl, benzo-fused cycloalkyl, orbenzo-fused heterocycloalkyl, are optionally substituted with one ormore substituents independently selected from halogen, hydroxy, amino,thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy, halogenatedalkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, or dialkylamino,—NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —OC(═O)NHalkyl,—NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl, —N(alkyl)SO₂alkyl,thioalkyl, halogenated thioalkyl, —SO₂alkyl, halogenated —SO₂alkyl,—NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or —OC(═O)N(alkyl)₂; s is aninteger from 0 to 2; m is an integer from 0 to 4; provided that the sumof m and s is an integer from 0 to 4; R⁶ and R⁷ are independentlyselected from the group consisting of: (a) (b)

provided that R⁴ is not

(c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —(C═O)OH, —C(═O)Oalkyl,—C(═O)Oaryl, —C(═O)Oheteroaryl, —(C═O)NH₂, —(C═O)NHalkyl,—(C═O)N(alkyl)₂, —C(═O)alkyl, -phenyl-OCH₃ or -phenyl-OC(═O)alkyl; (d)—C(═O)(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, or benzyl; (e)—C(═O)CH₂O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, or benzyl;(f) —C(═O)alkyl, or —C(═O)(C₃₋₆)cycloalkyl, wherein said —C(═O)alkyl,and —C(═O)(C₃₋₆)cycloalkyl may be optionally substituted with one ormore groups independently selected from: —OH, —Oalkyl, —Oalkylaryl,—NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, or —OC(═O)alkyl; (g) —C(═O)(CH₂)₁₋₃aryl, —C(═O)aryl,—C(═O)(CH₂)₁₋₃heteroaryl, or —C(═O)heteroaryl, wherein said—C(═O)(CH₂)₁₋₃aryl, —C(═O)aryl, —C(═O)(CH₂)₁₋₃heteroaryl, and—C(═O)heteroaryl may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl; (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with methyl, ethyl,—OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, or heterocycloalkyl; (hh)—C(═O)alkylOC(═O)alkyl-terminating with —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, or heterocycloalkyl; (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminatingwith H, methyl, ethyl, or benzyl; —C(═O)Oalkyl, or—C(═O)O(C₃₋₆)cycloalkyl, wherein said —C(═O)Oalkyl, and—C(═O)O(C₃₋₆)cycloalkyl may be optionally substituted with one or moregroups independently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, —OC(═O)alkyl,—C(═O)OH, —C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂;(k) —C(═O)O(CH₂)₁₋₃aryl, —C(═O)Oaryl, —C(═O)O(CH₂)₁₋₃heteroaryl, or—C(═O)Oheteroaryl, wherein said —C(═O)O(CH₂)₁₋₃aryl, —C(═O)Oaryl,—C(═O)O(CH₂)₁₋₃heteroaryl, or —C(═O)Oheteroaryl may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl; (l)—C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H, methyl, ethyl, benzyl,—CH₂CH₂NH₂, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl or —C(═O)alkyl; (m) —C(═O)NH₂,—C(═O)NH(C₁₋₂₀)alkyl, —C(═O)NH(C₃₋₆)cycloalkyl, or —C(═O)N(alkyl)₂,wherein said —C(═O)NH(C₁₋₂₀)alkyl, —C(═O)NH(C₃₋₆)cycloalkyl, and—C(═O)N(alkyl)₂ may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, —OC(═O)alkyl,—OC(═O)alkenyl, —NHC(═O)aryl, —C(═O)OH, —C(═O)Oalkyl, —C(═O)NH₂,—C(═O)NHalkyl, or —C(═O)N(alkyl)₂; and, wherein the aryl portion of said—NHC(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile; (n) —C(═O)NH(CH₂)₁₋₃aryl, —C(═O)NHaryl,—C(═O)NH(CH₂)₁₋₃heteroaryl, or —C(═O)NHheteroaryl, wherein said—C(═O)NH(CH₂)₁₋₃aryl, —C(═O)NHaryl, —C(═O)NH(CH₂)₁₋₃heteroaryl, and—C(═O)NHheteroaryl may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl; (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with H,methyl, ethyl, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃,—CH₂CH₂OC(═O)alkyl, or —C(═O)aryl; wherein the aryl portion of said—C(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile; (p) —C(═S)NH₂; (q) —C(═S)NHalkyl; (r)—C(═S)N(alkyl)₂; (s) —SO₂NH₂; (t) —SO₂NHalkyl; (u) —SO₂N(alkyl)₂; (v)—P(═O)(OCH3)2; and (w) —P(═O)(OCH₂CH₃)₂; provided that when R⁶ ispresent, R⁷ is absent; and provided that when R⁷ is present, R⁶ isabsent; R⁴ is selected from the group consisting of: H and

provided that if one of R⁶and R⁷ is

then R⁴ is H; L³ is absent or is a linking group selected from the groupconsisting of alkyldiyl, carbonyl or —SO₂—;

is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, aralkyl, a heteroaryl, aheterocycloalkyl, a nine to ten membered benzo-fused cycloalkyl, a nineto ten membered benzo-fused heteroaryl, and a nine to ten memberedbenzo-fused heterocycloalkyl; r is an integer from 0 to 4; and R⁵ isindependently selected from the group consisting of: alkyl, alkyl amino,alkyloxy, amino, —C(═O)NH₂, —C(═O)Oalkyl, —C(═O)OH, —CH₂OH, cyano,dialkylamino, halogen, halogenated alkyl, halogenated alkyloxy,halogenated SO₂-alkyl, halogenated thioalkyl, hydroxy, hydroxy alkyl,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —SO₂alkyl,—SO₂NH₂, thio, thioalkyl,

and —V—B¹⁰—W—B²⁰; wherein, V and W are each independently absent orselected from the group consisting of: —C(═O), —C(═O)N(alkyl)-,—C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—,—N(alkyl)C(═O)N(alkyl)-, —N(alkyl)C(═O)NH—, —N(alkyl)C(═O)O—,—N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-, —NHC(═O)NH—,—NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-, —OC(═O)NH—,—OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)- and —SO₂NH—; B¹⁰ is absent orselected from alkyl or alkenyl; B²⁰ is absent or selected from alkyl,alkenyl, or H; wherein, when B¹⁰ or B²⁰ is alkyl or alkenyl, the alkylor alkenyl group may be optionally substituted with one or more groupsindependently selected from: alkoxy, alkylamino, amino, cyano,dialkylamino, halogen, halogenated alkoxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl; and

is selected from the group consisting of: an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl, wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, is optionally substitutedwith one or more substituents independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated alkyl, halogenated —SO₂alkyl, halogenated thioalkyl,heteroaryl, hydroxy, hydroxy alkyl, —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —SO₂alkyl, thio or thioalkyl; or an optical isomer,enantiomer, diastereomer, racemate, or pharmaceutically acceptable saltthereof.
 30. A compound of Formula (II-GG):

wherein:

is selected from the group consisting of Formulae A-1, A-2 and A-3:

wherein Formula A-1 is attached on the b¹ side of Formula A-1 to the L²ring of Formula (II-GG) and optionally substituted with one substituentselected from the group consisting of Formulae A-1-a, A-1-b and A-1-c:

wherein Formula A-1-a is attached on the a¹ side to adjacent carbons onthe d¹or d² side of Formula A-1;

wherein Formula A-1-b is attached on the a²side to adjacent carbons onthe d¹or d² side of Formula A-1; and

wherein Formula A-1-c is attached on the a⁶ side to adjacent carbons onthe d¹or d² side of Formula A-1; wherein R⁸ is H or alkyl;

wherein Formula A-2 is attached on the b² side of Formula A-2 to the L²ring of Formula (II-GG), and A¹, A², A³, A⁴ are (i) —N—; or (ii) —C—substituted with H or alkoxy, wherein the alkoxy may be optionallyfurther substituted with alkoxy on a terminal carbon or up to 3 halogenatoms on a terminal carbon; provided that at least one and no more thantwo of A¹, A², A³, A⁴ are —N—; and

wherein Formula A-3 is attached on the b³ side of Formula A-3 to the L²ring of Formula (II-GG), and B¹, B² and B³are independently (i) —CH—optionally substituted with alkyl, aryl, alkoxy, or halogen, (ii) —S—;(iii) —O—; or (iv) —N—; provided that no more than one of B¹, B² or B³is —S-or —O—, and, provided that when one of B¹, B² or B³ is —S-or —O—,then the adjacent ring members are not —S-or —O—; R⁹ is independentlyselected from the group consisting of: alkoxy, alkyl, alkylamino, amino,cyano, dialkylamino, halogen, halogenated alkyl, halogenated alkyloxy,halogenated —SO₂alkyl, halogenated thioalkyl, hydroxy,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —SO₂alkyl, thioand thioalkyl; L² is a linking group selected from the group consistingof: —(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—, —O—, —O(CH₂)₁₋₄—,—OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-, —N(COalkyl)-,—N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and —N(SO₂aryl)-;wherein R¹⁰⁰ is selected from: alkyl, hydroxy, aryl, alkoxy, oxo, —NH₂,—NH(alkyl) —N(alkyl)₂, ═N(OH) or —NH₂OH; provided that when L² is—OCH(R¹⁰⁰)—, R¹⁰⁰ is alkoxy, and

is phenyl, R⁵ is not —C(═O)NH—NH₂; R¹⁰ is independently selected fromthe group consisting of

and —X¹-A²⁰-Y¹-A²¹; wherein X¹ and Y¹ are each independently absent orselected from the group consisting of: -(alkyl)C(═O)N(alkyl)-,—C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—,—N(alkyl)C(═O)NH—, —N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—,—NHC(═O)N(alkyl)-, —NHC(═O)NH, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O),—OC(═O)N(alkyl)-, —OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—,—SO₂N(alkyl)-, and —SO₂NH—; A²⁰ is absent or selected from alkyl oralkenyl; and A²¹ is selected from alkyl, alkenyl, or H; wherein when A²⁰or A²¹ is alkyl or alkenyl, the alkyl or alkenyl may be optionallysubstituted with one or more groups independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated —SO₂alkyl, halogenated thioalkyl, hydroxy,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl;

is selected from the group consisting of aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, nine to tenmembered benzo-fused cycloalkyl, and nine to ten membered benzo-fusedheterocycloalkyl; wherein, the aryl, cycloalkyl, partially unsaturatedcarbocycle, heteroaryl, heterocycloalkyl, benzo-fused cycloalkyl, orbenzo-fused heterocycloalkyl, are optionally substituted with one ormore substituents independently selected from halogen, hydroxy, amino,thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy, halogenatedalkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, or dialkylamino,—NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —OC(═O)NHalkyl,—NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl, —N(alkyl)SO₂alkyl,thioalkyl, halogenated thioalkyl, —SO₂alkyl, halogenated —SO₂alkyl,—NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or —OC(═O)N(alkyl)₂; s is aninteger from 0 to 2; m is an integer from 0 to 4; provided that when

is not substituted with Formulae A-1-a, A-1-b or A-1-c, the sum of m ands is an integer from 0 to 4, and when

is substituted with one of Formulae A-1-a, A-1-b, or A-1-c, the sum of mand s is an integer from 0 to 2; R⁶ and R⁷ are independently selectedfrom the group consisting of: (a) (b)

provided that R⁴ is not

(c) alkyl (d) —C(═O)alkylOH; and (e) —C(═O)CH₂Oalkoxy; provided thatwhen R⁶ is present, R⁷ is absent; and provided that when R⁷ is present,R⁶ is absent; R⁴ is selected from the group consisting of: H and

provided that if one of R⁶and R⁷ is

then R⁴ is H; L³ is absent or is a linking group selected from the groupconsisting of alkyldiyl, carbonyl or —SO₂—;

is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, aralkyl, a heteroaryl, aheterocycloalkyl, a nine to ten membered benzo-fused cycloalkyl, a nineto ten membered benzo-fused heteroaryl, and a nine to ten memberedbenzo-fused heterocycloalkyl; r is an integer from 0 to 4; and R⁵ isindependently selected from the group consisting of: alkyl, alkyl amino,alkyloxy, amino, —C(═O)NH₂, —C(═O)Oalkyl, —C(═O)OH, —CH₂OH, cyano,dialkylamino, halogen, halogenated alkyl, halogenated alkyloxy,halogenated SO₂-alkyl, halogenated thioalkyl, hydroxy, hydroxy alkyl,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —SO₂alkyl,—SO₂NH₂, thio, thioalkyl,

and —V—B¹⁰—W—B²⁰; wherein, V and W are each independently absent orselected from the group consisting of: —C(═O), —C(═O)N(alkyl)-,—C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—,—N(alkyl)C(═O)N(alkyl)-, —N(alkyl)C(═O)NH—, —N(alkyl)C(═O)O—,—N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-, —NHC(═O)NH—,—NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-, —OC(═O)NH—,—OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)- and —SO₂NH—; B¹⁰ is absent orselected from alkyl or alkenyl; B²⁰ is absent or selected from alkyl,alkenyl, or H; wherein, when B¹⁰ or B²⁰ is alkyl or alkenyl, the alkylor alkenyl group may be optionally substituted with one or more groupsindependently selected from: alkoxy, alkylamino, amino, cyano,dialkylamino, halogen, halogenated alkoxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl; and

is selected from the group consisting of: an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl, wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, is optionally substitutedwith one or more substituents independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated alkyl, halogenated —SO₂alkyl, halogenated thioalkyl,heteroaryl, hydroxy, hydroxy alkyl, —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —SO₂alkyl, thio or thioalkyl; or an optical isomer,enantiomer, diastereomer, racemate, or pharmaceutically acceptable saltthereof.
 31. A compound as in claim 30, wherein R⁷ is absent, and R6 isselected from the group consisting of: (a) (b)

provided that R⁴ is not

(c) methyl (d) —C(═O)CH₂OH; and (e) —C(═O)CH₂Omethoxy;
 32. A compound ofFormula (II-HH):

wherein:

is selected from the group consisting of Formulae A-1, A-2 and A-3:

wherein Formula A-1 is attached on the b¹ side of Formula A-1 to the L²ring of formula (II-HH) and optionally substituted with one substituentselected from the group consisting of Formulae A-1-a, A-1-b and A-1-c:

wherein Formula A-1-a is attached on the a¹ side to adjacent carbons onthe d¹or d² side of Formula A-1;

wherein Formula A-1-b is attached on the a side to adjacent carbons onthe d¹or d² side of Formula A-1; and

wherein Formula A-1-c is attached on the a⁶ side to adjacent carbons onthe d¹or d² side of Formula A-1; wherein R⁸ is H or alkyl;

wherein Formula A-2 is attached on the b² side of Formula A-2 to the L²ring of formula (II-HH), and A¹, A², A³, A⁴ are (i) —N—; or (ii) —C—substituted with H or alkoxy, wherein the alkoxy may be optionallyfurther substituted with alkoxy on a terminal carbon or up to 3 halogenatoms on a terminal carbon; provided that at least one and no more thantwo of A¹, A², A³, A⁴ are —N—; and

wherein Formula A-3 is attached on the b³ side of Formula A-3 to the L²ring of formula (II-HH), and B¹, B² and B³ are independently (i) —CH—optionally substituted with alkyl, aryl, alkoxy, or halogen, (ii) —S—;(iii) —O—; or (iv) —N—; provided that no more than one of B¹, B² or B³is —S-or —O—, and, provided that when one of B¹, B² or B³ is —S-or —O—,then the adjacent ring members are not —S-or —O—; R⁹ is independentlyselected from the group consisting of: alkoxy, alkyl, alkylamino, amino,cyano, dialkylamino, halogen, halogenated alkyl, halogenated alkyloxy,halogenated —SO₂alkyl, halogenated thioalkyl, hydroxy,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —SO₂alkyl, thioand thioalkyl; L² is a linking group selected from the group consistingof: —(CH₂)—, —CH(CH₃)—, —CH(CH₂CH₃)—, and —O—, provided that when L² is—O—, neither R⁶ nor R⁷ is —CH₃; R¹⁰ is independently selected from thegroup consisting of

and —X¹-A²⁰-Y¹-A²¹; wherein X¹ and Y¹ are each independently absent orselected from the group consisting of: (alkyl)C(═O)N(alkyl)-,—C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—,—N(alkyl)C(═O)NH—, —N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—,—NHC(═O)N(alkyl)-, —NHC(═O)NH, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O),—OC(═O)N(alkyl)-, —OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—,—SO₂N(alkyl)-, and —SO₂NH—; A²⁰ is absent or selected from alkyl oralkenyl; and A²¹ is selected from alkyl, alkenyl, or H; wherein when A²⁰or A²¹ is alkyl or alkenyl, the alkyl or alkenyl may be optionallysubstituted with one or more groups independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated —SO₂alkyl, halogenated thioalkyl, hydroxy,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl;

is selected from the group consisting of aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, nine to tenmembered benzo-fused cycloalkyl, and nine to ten membered benzo-fusedheterocycloalkyl; wherein, the aryl, cycloalkyl, partially unsaturatedcarbocycle, heteroaryl, heterocycloalkyl, benzo-fused cycloalkyl, orbenzo-fused heterocycloalkyl, are optionally substituted with one ormore substituents independently selected from halogen, hydroxy, amino,thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy, halogenatedalkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, or dialkylamino,—NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —OC(═O)NHalkyl,—NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl, —N(alkyl)SO₂alkyl,thioalkyl, halogenated thioalkyl, —SO₂alkyl, halogenated —SO₂alkyl,—NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or —OC(═O)N(alkyl)₂; s is aninteger from 0 to 2; m is an integer from 0 to 4; provided that when

is not substituted with Formulae A-1-a, A-1-b or A-1-c, the sum of m ands is an integer from 0 to 4, and when

is substituted with one of Formulae A-1-a, A-1-b, or A-1-c, the sum of mand s is an integer from 0 to 2; R⁶ and R⁷ are independently selectedfrom the group consisting of: (a) (b)

provided that R⁴ is not

(c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —(C═O)OH, —C(═O)Oalkyl,—C(═O)Oaryl, —C(═O)Oheteroaryl, —(C═O)NH₂, —(C═O)NHalkyl,—(C═O)N(alkyl)₂, —C(═O)alkyl, —phenyl-OCH₃ or -phenyl-OC(═O)alkyl; (d)—C(═O)(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, or benzyl; (e)—C(═O)CH₂O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, or benzyl;(f) —C(═O)alkyl, or —C(═O)(C₃₋₆)cycloalkyl, wherein said —C(═O)alkyl,and —C(═O)(C₃₋₆)cycloalkyl may be optionally substituted with one ormore groups independently selected from: —OH, —Oalkyl, —Oalkylaryl,—NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, or —OC(═O)alkyl; (g) —C(═O)(CH₂)₁₋₃aryl, —C(═O)aryl,—C(═O)(CH₂)₁₋₃heteroaryl, or —C(═O)heteroaryl, wherein said—C(═O)(CH₂)₁₋₃aryl, —C(═O)aryl, —C(═O)(CH₂)₁₋₃heteroaryl, and—C(═O)heteroaryl may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl; (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with methyl, ethyl,—OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, or heterocycloalkyl; (hh)—C(═O)alkylOC(═O)alkyl-terminating with —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, or heterocycloalkyl; (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminatingwith H, methyl, ethyl, or benzyl; (j) —C(═O)Oalkyl, or—C(═O)O(C₃₋₆)cycloalkyl, wherein said —C(═O)Oalkyl, and—C(═O)O(C₃₋₆)cycloalkyl may be optionally substituted with one or moregroups independently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, —OC(═O)alkyl,—C(═O)OH, —C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂;(k) —C(═O)O(CH₂)₁₋₃aryl, —C(═O)Oaryl, —C(═O)O(CH₂)₁₋₃heteroaryl, or—C(═O)Oheteroaryl, wherein said —C(═O)O(CH₂)₁₋₃aryl, —C(═O)Oaryl,—C(═O)O(CH₂)₁₋₃heteroaryl, or —C(═O)Oheteroaryl may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl; (l)—C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H, methyl, ethyl, benzyl,—CH₂CH₂NH₂, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl or —C(═O)alkyl; (m) —C(═O)NH₂,—C(═O)NH(C₁₋₂₀)alkyl, —C(═O)NH(C₃₋₆)cycloalkyl, or —C(═O)N(alkyl)₂,wherein said —C(═O)NH(C₁₋₂₀)alkyl, —C(═O)NH(C₃₋₆)cycloalkyl, and—C(═O)N(alkyl)₂ may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, —OC(═O)alkyl,—OC(═O)alkenyl, —NHC(═O)aryl, —C(═O)OH, —C(═O)Oalkyl, —C(═O)NH₂,—C(═O)NHalkyl, or —C(═O)N(alkyl)₂; and, wherein the aryl portion of said—NHC(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile; (n) —C(═O)NH(CH₂)₁₋₃aryl, —C(═O)NHaryl,—C(═O)NH(CH₂)₁₋₃heteroaryl, or —C(═O)NHheteroaryl, wherein said—C(═O)NH(CH₂)₁₋₃aryl, —C(═O)NHaryl, —C(═O)NH(CH₂)₁₋₃heteroaryl, and—C(═O)NHheteroaryl may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl; (o) —C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with H,methyl, ethyl, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃,—CH₂CH₂OC(═O)alkyl, or —C(═O)aryl; wherein the aryl portion of said—C(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH , —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile; (p) —C(═S)NH₂; (q) —C(═S)NHalkyl; (r)—C(═S)N(alkyl)₂; (s) —SO₂NH₂; (t) —SO₂NHalkyl; (u) —SO₂N(alkyl)₂; (v)—P(═O)(OCH₃)₂; and (w) —P(═O)(OCH₂CH₃)₂; provided that when R⁶ ispresent, R⁷ is absent; and provided that when R⁷ is present, R⁶ isabsent; R⁴ is selected from the group consisting of: H and

provided that if one of R⁶and R⁷ is

then R⁴ is H; L³ is absent or is a linking group selected from the groupconsisting of alkyldiyl, carbonyl or —SO₂—;

is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, aralkyl, a heteroaryl, aheterocycloalkyl, a nine to ten membered benzo-fused cycloalkyl, a nineto ten membered benzo-fused heteroaryl, and a nine to ten memberedbenzo-fused heterocycloalkyl; r is an integer from 0 to 4; and R⁵ isindependently selected from the group consisting of: alkyl, alkyl amino,alkyloxy, amino, —C(═O)NH₂, —C(═O)Oalkyl, —C(═O)OH, —CH₂OH, cyano,dialkylamino, halogen, halogenated alkyl, halogenated alkyloxy,halogenated SO₂-alkyl, halogenated thioalkyl, hydroxy, hydroxy alkyl,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —SO₂alkyl,—SO₂NH₂, thio, thioalkyl,

and —V—B¹⁰—W—B²⁰; wherein, V and W are each independently absent orselected from the group consisting of: —C(═O), —C(═O)N(alkyl)-,—C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—,—N(alkyl)C(═O)N(alkyl)-, —N(alkyl)C(═O)NH—, —N(alkyl)C(═O)O—,—N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-, —NHC(═O)NH—,—NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-, —OC(═O)NH—,—OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)- and —SO₂NH—; B¹⁰ is absent orselected from alkyl or alkenyl; B²⁰ is absent or selected from alkyl,alkenyl, or H; wherein, when B¹⁰ or B²⁰ is alkyl or alkenyl, the alkylor alkenyl group may be optionally substituted with one or more groupsindependently selected from: alkoxy, alkylamino, amino, cyano,dialkylamino, halogen, halogenated alkoxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl; and

is selected from the group consisting of: an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl, wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, is optionally substitutedwith one or more substituents independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated alkyl, halogenated —SO₂alkyl, halogenated thioalkyl,heteroaryl, hydroxy, hydroxy alkyl, —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —SO₂alkyl, thio or thioalkyl; or an optical isomer,enantiomer, diastereomer, racemate, or pharmaceutically acceptable saltthereof.
 33. A compound as in claim 32, wherein L² is a linking groupselected from the group consisting of: —(CH₂)—, —CH(CH₃)—, —CH(CH₂CH₃)—.34. A compound of Formula (II-JJ):

wherein R⁶ and R⁷ are independently selected from the group consistingof: (a) (b)

provided that R⁴ is not

(c) —CH₂— substituted with one group selected from: —H, -methyl,—Oalkyl, —CH₂OH, —CH(CH₃)OH, —O(C═O)alkyl, —(C═O)OH, —C(═O)Oalkyl,—C(═O)Oaryl, —C(═O)Oheteroaryl, —(C═O)NH₂, —(C═O)NHalkyl,—(C═O)N(alkyl)₂, —C(═O)alkyl, -phenyl-OCH₃ or -phenyl-OC(═O)alkyl; (d)—C(═O)(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, or benzyl; (e)—C(═O)CH₂O(CH₂CH₂O—)₁₋₁₀ terminating with H, methyl, ethyl, or benzyl;(f) —C(═O)alkyl, or —C(═O)(C₃₋₆)cycloalkyl, wherein said —C(═O)alkyl,and —C(═O)(C₃₋₆)cycloalkyl may be optionally substituted with one ormore groups independently selected from: —OH, —Oalkyl, —Oalkylaryl,—NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, or —OC(═O)alkyl; (g) —C(═O)(CH₂)₁₋₃aryl, —C(═O)aryl,—C(═O)(CH₂)₁₋₃heteroaryl, or —C(═O)heteroaryl, wherein said—C(═O)(CH₂)₁₋₃aryl, —C(═O)aryl, —C(═O)(CH₂)₁₋₃heteroaryl, and—C(═O)heteroaryl may be optionally substituted with one or more groupsindependently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂,heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, halogen, nitrile, or—OC(═O)alkyl; (h) —C(═O)(CH₂)₁₋₆C(═O)— terminating with methyl, ethyl,—OH, —Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, or heterocycloalkyl; (hh)—C(═O)alkylOC(═O)alkyl-terminating with —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, or heterocycloalkyl; (i) —C(═O)O(CH₂CH₂O—)₁₋₁₀ terminatingwith H, methyl, ethyl, or benzyl; (j) —C(═O)Oalkyl, or—C(═O)O(C₃₋₆)cycloalkyl, wherein said —C(═O)Oalkyl, and—C(═O)O(C₃₋₆)cycloalkyl may be optionally substituted with one or moregroups independently selected from: —OH, —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl, —NHSO₂alkyl, —OC(═O)alkyl,—C(═O)OH, —C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂;(k) —C(═O)O(CH₂)₁₋₃aryl, —C(═O)Oaryl, —C(═O)O(CH₂)₁₋₃heteroaryl, or—C(═O)Oheteroaryl, wherein said —C(═O)O(CH₂)₁₋₃aryl, —C(═O)Oaryl,—C(═O)O(CH₂)₁₋₃heteroaryl, or —C(═O)Oheteroaryl may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl; (l)—C(═O)NH(CH₂CH₂O—)₁₋₁₀ terminating with —H, methyl, ethyl, benzyl,—CH₂CH₂NH₂, —CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl or —C(═O)alkyl; (m)—C(═O)NH₂,C(═O)NH(C₁₋₂₀)alkyl, —C(═O)NH(C₃₋₆)cycloalkyl, or—C(═O)N(alkyl)₂, wherein said —C(═O)NH(C₁₋₂₀)alkyl,—C(═O)NH(C₃₋₆)cycloalkyl, and —C(═O)N(alkyl)₂ may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)alkenyl, —NHC(═O)aryl, —C(═O)OH,—C(═O)Oalkyl, —C(═O)NH₂, —C(═O)NHalkyl, or —C(═O)N(alkyl)₂; and, whereinthe aryl portion of said —NHC(═O)aryl may be optionally substituted withone or more groups independently selected from: alkyl, —OH, —Oalkyl,—NH₂, —NHalkyl, —N(alkyl)₂, halogen or nitrile; (n)—C(═O)NH(CH₂)₁₋₃aryl, —C(═O)NHaryl, —C(═O)NH(CH₂)₁₋₃heteroaryl, or—C(═O)NHheteroaryl, wherein said —C(═O)NH(CH₂)₁₋₃aryl, —C(═O)NHaryl,—C(═O)NH(CH₂)₁₋₃heteroaryl, and —C(═O)NHheteroaryl may be optionallysubstituted with one or more groups independently selected from: —OH,—Oalkyl, —NH₂, —NHalkyl, —N(alkyl)₂, heterocycloalkyl, —NHC(═O)alkyl,—NHSO₂alkyl, halogen, nitrile, or —OC(═O)alkyl; (o)—C(═O)NHCH₂CH₂NH(CH₂CH₂NH—)₀₋₃ terminating with H, methyl, ethyl,—CH₂CH₂NHalkyl, —CH₂CH₂N(alkyl)₂, —CH₂CH₂-1-pyrrolidinyl,—CH₂CH₂-1-piperidinyl, —CH₂CH₂-4-morpholinyl, —CH₂CH₂-1-piperazinyl,—CH₂CH₂-1-(4-CH₃)-piperazinyl, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃,—CH₂CH₂OC(═O)alkyl, or —C(═O)aryl; wherein the aryl portion of said—C(═O)aryl may be optionally substituted with one or more groupsindependently selected from: alkyl, —OH , —Oalkyl, —NH₂, —NHalkyl,—N(alkyl)₂, halogen or nitrile; (p) —C(═S)NH₂; (q) —C(═S)NHalkyl; (r)—C(═S)N(alkyl)₂; (s) —SO₂NH₂; (t) —SO₂NHalkyl; (u) —SO₂N(alkyl)₂; (v)—P(═O)(OCH₃)₂; and (w) —P(═O)(OCH₂CH₃)₂; provided that when R⁶ ispresent, R⁷ is absent; and provided that when R⁷ is present, R⁶ isabsent; R⁴ is selected from the group consisting of: H and

provided that if one of R⁶and R⁷ is

then R⁴ is H; or an optical isomer, enantiomer, diastereomer, racemate,or pharmaceutically acceptable salt thereof.
 35. A compound selectedfrom the group consisting of:


36. A compound selected from the group consisting of:


37. A compound of the following formula:


38. A compound of the following formula:


39. A compound of the following formula:


40. A compound of the following formula:


41. A compound selected from the group consisting of:1-[3-(3-Chloro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;[7-Methoxy-6-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-methoxy-phenyl)-amine;1-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;(3-Bromo-phenyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;1-[3-(3-Fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;3-[3-(2,6-Dichloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;(3-Methoxy-phenyl)-[7-methoxy-6-(3-pyrrolidin-1-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(6,7-Diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;3-[3-(3-Fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[3-(3-Chloro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;(2,6-Dichloro-benzyl)-(6,7-diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;1-[3-(3-Chloro-4-fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;3-[3-(2,6-Dichloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;(2-Chloro-benzyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Chloro-4-fluoro-phenyl)-[6-(3-dimethylamino-propoxy)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-m-tolyl-amine;3-[3-(2-Chloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;1-[3-(2,6-Dichloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;3-[3-(3-Chloro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;(2-Bromo-benzyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Bromo-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;1-[6-Ethoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(2-methyl-benzyl)-amine;1-[7-Methoxy-3-(pyridin-3-ylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;(3-Chloro-phenyl)-{7-methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl}-amine;[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-chloro-phenyl)-amine;3-[7-(3-Hydroxy-propoxy)-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;(3-Chloro-phenyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methylsulfanyl-phenyl)-amine;(3-Fluoro-phenyl)-[6-(3-imidazol-1-yl-propoxy)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;3-[3-(2,6-Difluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[3-(3-Chloro-phenylamino)-7-(3-hydroxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(2-Chloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(2,6-Difluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;1-[6-Ethoxy-3-(3-fluoro-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-fluoro-phenyl)-amine;(3-Fluoro-phenyl)-(7-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(2,5-Difluoro-phenyl)-(6-fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-methoxy-phenyl)-amine;(3-Fluoro-phenyl)-(4-methoxy-2-methyl-8a,9-dihydro-3-oxa-1,6,7-triaza-cyclopenta[b]-as-indacen-8-yl)-amine;1-[3-(2-Chloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-benzamide;(3-Chloro-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;3-(3-Fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-ol;3-[3-(3-Fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[7-Ethoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;{7-Methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl}-(3-methoxy-phenyl)-amine;(3-Fluoro-phenyl)-{7-methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl}-amine;[6-(3-Dimethylamino-propoxy)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-fluoro-phenyl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-phenyl-amine;(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4-fluoro-phenyl)-amine;(3-Bromo-phenyl)-(6,7-dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;1-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-2-methoxy-ethanone;1-[3-(2,6-Difluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;3-[3-(3-Fluoro-phenylamino)-7-(3-hydroxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[7-Methoxy-6-(3-pyrrolidin-1-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino]-benzoicacid methyl ester;(2,6-Difluoro-benzyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;1-[6-Ethoxy-3-(pyridin-3-ylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[3-(2-Fluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;(3-Bromo-phenyl)-(6,7-dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(2,4-Dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;3-[3-(3-Ethoxy-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[3-(3-Chloro-phenylamino)-6-ethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol;(2-Chloro-pyridin-3-yl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(7-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;[5-(3-Dimethylamino-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-fluoro-phenyl)-amine;(3-Bromo-phenyl)-(6-fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(2,4-Dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;Methoxy-acetic acid2-[3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-2-oxo-ethylester;(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4-fluoro-phenyl)-amine;3-[3-(3-Ethoxy-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;(3,5-Difluoro-phenyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;3-[3-(3-Chloro-4-fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;(3-Fluoro-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Ethoxy-phenyl)-(4-ethyl-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;3-[3-(3-Chloro-4-fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;1-[6-Ethoxy-3-(3-ethoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;3-[3-(2-Fluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-isopropoxy-phenyl)-amine;3-[6-Ethoxy-3-(3-fluoro-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol;(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4-fluoro-phenyl)-amine;3-[3-(2-Fluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[7-Ethoxy-3-(3-fluoro-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-m-tolyl-amine;3-[6-Ethoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol;(3-Chloro-4-fluoro-phenyl)-(6,7-diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;N3-(3-Fluoro-phenyl)-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazole-3,5-diamine;(6-Bromo-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;(3-Chloro-4-fluoro-phenyl)-(6-fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-methoxy-phenyl)-amine;(3-Fluoro-phenyl)-[7-methoxy-6-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Fluoro-phenyl)-(7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Fluoro-phenyl)-[7-methoxy-6-(3-pyrrolidin-1-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;Acetic acid3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-ylmethylester;[6-(3-Methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-phenyl-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-ethoxy-phenyl)-amine;(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridin-3-yl-amine;3-[3-(3-Chloro-4-fluoro-phenylamino)-7-(3-hydroxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;(3-Fluoro-phenyl)-(2H-8-oxa-2,3-diaza-cyclopenta[a]inden-1-yl)-amine;(3-Chloro-4-fluoro-phenyl)-[7-methoxy-6-(3-pyrrolidin-1-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;3-[7-(3-Hydroxy-propoxy)-3-(pyridin-3-ylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;(6,7-Diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-benzoicacid methyl ester;(2,5-Dimethoxy-phenyl)-(6-fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridin-3-yl-amine;(3-Bromo-phenyl)-[6-(4-methyl-piperazin-1-yl)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(2,5-Dichloro-benzyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-pyridin-3-yl-amine;(3-Chloro-phenyl)-[6-(4-methyl-piperazin-1-yl)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;Acetic acid2-[3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-2-oxo-ethylester; (7-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-phenyl-amine;(2-Chloro-benzyl)-(6,7-diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;1-[3-(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-phenyl]-ethanol;(6-Bromo-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(7-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-phenyl-amine;N3-(3-Chloro-phenyl)-2,4-dihydro-indeno[1,2-c]pyrazole-3,6-diamine;1-[3-(7-Methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-phenyl]-ethanol;(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-ethoxy-phenyl)-amine;(3-Bromo-phenyl)-(4-ethyl-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;N3-(3-Methoxy-phenyl)-2,4-dihydro-indeno[1,2-c]pyrazole-3,6-diamine;3-[3-(3-Ethoxy-phenylamino)-7-(3-hydroxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;4-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-4-oxo-butyramide;(4-Methoxy-2-methyl-6,9-dihydro-3-oxa-1,6,7-triaza-cyclopenta[b]-as-indacen-8-yl)-(3-methoxy-phenyl)-amine;(7-Methoxy-2H-8-oxa-2,3-diaza-cyclopenta[a]inden-1-yl)-phenyl-amine;3-[3-(2-Methyl-benzylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-5-yloxy]-propan-1-ol;(6,7-Diethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;3-[7-Ethoxy-3-(pyridin-3-ylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;(2,6-Dichloro-benzyl)-[5-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;3-(3-Fluoro-phenylamino)-6-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-7-ol;[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-chloro-4-fluoro-phenyl)-amine;(5-Chloro-2-methoxy-phenyl)-(2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(4-Fluoro-phenyl)-(7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4-methoxy-phenyl)-amine;(2,6-Dichloro-benzyl)-(6,7-dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;Butyric acid3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-ylmethylester;5-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-5-oxo-pentanoicacid methylamide;1-[3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-phenyl]-ethanol;(3-Fluoro-phenyl)-(5-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Chloro-4-methoxy-phenyl)-(7-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-phenol;4-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-4-oxo-butyricacid;1-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-2-yl]-3-pyrrolidin-1-yl-propane-1,3-dione;N-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-5-yl]-acetamide;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-ethyl-phenyl)-amine;[3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-phenyl]-methanol;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3,5-dimethoxy-phenyl)-amine;(3-Benzyloxy-phenyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Chloro-4-fluoro-phenyl)-[6-(3-imidazol-1-yl-propoxy)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(6,7-Diisopropoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;3-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-3-oxo-propionicacid ethyl ester;3-[6-Ethoxy-3-(3-ethoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol;[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-pyridin-3-yl-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-trifluoromethyl-phenyl)-amine;(2-Chloro-pyridin-3-yl)-(6,7-dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;3-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino]-benzoicacid methyl ester;(3,5-Dimethoxy-phenyl)-(6-fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;1-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-2-hydroxy-ethanone;(3-Bromo-phenyl)-(4-ethyl-6,7-dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(5,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(3-methoxy-phenyly-amine;(6-Chloro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;(2,4-Dihydro-indeno[1,2-c]pyrazol-3-yl)-(2,5-dimethoxy-phenyl)-amine;(3-Chloro-4-fluoro-phenyl)-(6-fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6-Chloro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridin-3-yl-amine;(7-Methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-phenyl-amine;3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazole-2-carboxylicacid 4-fluoro-phenyl ester;3-[3-(3-Chloro-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-5-yloxy]-propan-1-ol;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(2-methyl-benzyl)-amine;3-[7-Methoxy-3-(pyridin-3-ylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;(3,4-Dimethoxy-phenyl)-(6-fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;3-[6-Ethoxy-3-(pyridin-3-ylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol;3-[3-(3-Bromo-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-5-yloxy]-propane-1,2-diol;(2,5-Difluoro-phenyl)-(7-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-trifluoromethylsulfanyl-phenyl)-amine;(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4-trifluoromethyl-phenyl)-amine;(3-Bromo-phenyl)-(4-ethyl-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(5-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-phenyl-amine;(2,9-Dihydro-5,7-dioxa-2,3-diaza-cyclopenta[a]-s-indacen-1-yl)-(3-methoxy-phenyl)-amine;(2,3-Dimethoxy-benzyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Chloro-4-fluoro-phenyl)-(2H-8-oxa-2,3-diaza-cyclopenta[a]inden-1-yl)-amine;3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazole-1-carboxylicacid (2-morpholin-4-yl-ethyl)-amide;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(2-fluoro-phenyl)-amine;[6-(3-Dimethylamino-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-fluoro-phenyl)-amine;(3-Chloro-4-fluoro-phenyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Chloro-phenyl)-(2,9-dihydro-5,7-dioxa-2,3-diaza-cyclopenta[a]-s-indacen-1-yl)-amine;(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(1H-indol-5-yl)-amine;(3-Chloro-phenyl)-(4-ethyl-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;3-[3-(3-Chloro-4-fluoro-phenylamino)-6-ethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol;(3-Bromo-phenyl)-(2,9-dihydro-5,7-dioxa-2,3-diaza-cyclopenta[a]-s-indacen-1-yl)-amine;Isobutyric acid2-[3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-2-oxo-ethylester;(5,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(3-ethoxy-phenyl)-amine;(6,7-Diethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazole-1-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide;3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-benzoicacid ethyl ester;(6-Chloro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(6,7-Diisopropoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;(2,5-Difluoro-phenyl)-(6-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(2-fluoro-benzyl)-amine;(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-phenyl-amine;(3-Chloro-4-fluoro-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Bromo-phenyl)-(6-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Bromo-phenyl)-(6,7-diethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-benzyl)-amine;(1H-Indol-5-yl)-(7-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;1-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-2-yl]-ethanone;(2,9-Dihydro-5,7-dioxa-2,3-diaza-cyclopenta[a]-s-indacen-1-yl)-(3-fluoro-phenyl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(2-trifluoromethyl-benzyl)-amine;Acetic acid3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-2-ylmethylester;(3-Chloro-benzyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Diethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4-fluoro-phenyl)-amine;(4-Ethyl-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;3-[(6,7-Dimethoxy-3-phenylamino-4H-indeno[1,2-c]pyrazole-2-carbonyl)-amino]-propionicacid ethyl ester;(2,5-Difluoro-phenyl)-(4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridin-2-yl-amine;(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-phenyl-amine;(3-Chloro-4-fluoro-phenyl)-[7-methoxy-6-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;Benzyl-(6,7-diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Chloro-phenyl)-(5,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine;(6,7-Diethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridin-3-yl-amine;(7-Benzyloxy-6-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(6-Bromo-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;N3-Phenyl-2,4-dihydro-indeno[1,2-c]pyrazole-3,6-diamine;3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazole-1-carboxylicacid 4-chloro-phenyl ester;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(2-fluoro-benzyl)-amine;3-[3-(2,6-Difluoro-benzylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-5-yloxy]-propan-1-ol;(3-Methoxy-phenyl)-[6-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;and[6-(3-Dimethylamino-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(4-fluoro-phenyl)-amine.42. A compound selected from the group consisting of:(5-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-phenyl-amine;3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-benzoicacid methyl ester;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(2-fluoro-phenyl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4-fluoro-phenyl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(7-Methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-phenyl-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-trifluoromethyl-phenyl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridin-3-yl-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-m-tolyl-amine;[3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-phenyl]-methanol;3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-phenol;(7-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-phenyl-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3,5-dimethoxy-phenyl)-amine;(3-Bromo-phenyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Chloro-4-fluoro-phenyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Benzyloxy-phenyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;[5-(3-Dimethylamino-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-fluoro-phenyl)-amine;(2,9-Dihydro-5,7-dioxa-2,3-diaza-cyclopenta[a]-s-indacen-1-yl)-(3-methoxy-phenyl)-amine;3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-benzamide;N3-(3-Methoxy-phenyl)-2,4-dihydro-indeno[1,2-c]pyrazole-3,6-diamine;N3-(3-Chloro-phenyl)-2,4-dihydro-indeno[1,2-c]pyrazole-3,6-diamine;(3-Bromo-phenyl)-[6-(4-methyl-piperazin-1-yl)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Chloro-phenyl)-[6-(4-methyl-piperazin-1-yl)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Chloro-phenyl)-(2,9-dihydro-5,7-dioxa-2,3-diaza-cyclopenta[a]-s-indacen-1-yl)-amine;[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-pyridin-3-yl-amine;(3-Bromo-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-methoxy-phenyl)-amine;(3-Chloro-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;3-[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino]-benzoicacid methyl ester;(3-Fluoro-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;[6-(3-Methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-phenyl-amine;(3-Methoxy-phenyl)-[7-methoxy-6-(3-pyrrolidin-1-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;3-[7-Methoxy-6-(3-pyrrolidin-1-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino]-benzoicacid methyl ester;[6-(3-Dimethylamino-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-fluoro-phenyl)-amine;(6,7-Diisopropoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(4-Fluoro-phenyl)-(7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Fluoro-phenyl)-(7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Fluoro-phenyl)-[7-methoxy-6-(3-pyrrolidin-1-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Chloro-4-fluoro-phenyl)-[7-methoxy-6-(3-pyrrolidin-1-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Fluoro-phenyl)-(7-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(2,5-Difluoro-phenyl)-(7-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6-Chloro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridin-3-yl-amine;(6-Chloro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;[6-(3-Dimethylamino-propoxy)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-fluoro-phenyl)-amine;(3-Chloro-4-fluoro-phenyl)-[6-(3-dimethylamino-propoxy)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Chloro-4-fluoro-phenyl)-(6-fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(2,5-Dimethoxy-phenyl)-(6-fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3,5-Dimethoxy-phenyl)-(6-fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3,4-Dimethoxy-phenyl)-(6-fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3,5-Difluoro-phenyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methylsulfanyl-phenyl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-ethyl-phenyl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-trifluoromethylsulfanyl-phenyl)-amine;(3-Chloro-phenyl)-{7-methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl}-amine;{7-Methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl}-(3-methoxy-phenyl)-amine;(3-Fluoro-phenyl)-{7-methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl}-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(2-methyl-benzyl)-amine;(3-Fluoro-phenyl)-[6-(3-imidazol-1-yl-propoxy)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Chloro-4-fluoro-phenyl)-[6-(3-imidazol-1-yl-propoxy)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(2-Chloro-benzyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(5,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(3-methoxy-phenyl)-amine;(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4-methoxy-phenyl)-amine;(2,5-Difluoro-phenyl)-(6-fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4-trifluoromethyl-phenyl)-amine;(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-m-tolyl-amine;(3-Fluoro-phenyl)-[7-methoxy-6-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;[7-Methoxy-6-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-methoxy-phenyl)-amine;(6,7-Diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;(3-Chloro-4-fluoro-phenyl)-(6,7-diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;(3-Bromo-phenyl)-(6,7-dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;3-[3-(3-Chloro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[3-(3-Chloro-4-fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[3-(3-Fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[7-Methoxy-3-(pyridin-3-ylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[3-(3-Fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(3-Chloro-4-fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(3-Chloro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;1-[3-(3-Fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-phenyl]-ethanol;1-[3-(3-Chloro-4-fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[7-Methoxy-3-(pyridin-3-ylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[3-(3-Chloro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-fluoro-phenyl)-amine;[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-methoxy-phenyl)-amine;[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-chloro-phenyl)-amine;[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-pyridin-3-yl-amine;[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-chloro-4-fluoro-phenyl)-amine;1-[3-(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-phenyl]-ethanol;(2-Chloro-benzyl)-(6,7-diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(2,6-Dichloro-benzyl)-(6,7-diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(7-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-phenyl-amine;(3-Chloro-4-methoxy-phenyl)-(7-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;1-[3-(7-Methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-phenyl]-ethanol;(2,6-Difluoro-benzyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(2,3-Dimethoxy-benzyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(2,5-Dichloro-benzyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(7-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(2,4-Dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(2,4-Dihydro-indeno[1,2-c]pyrazol-3-yl)-(2,5-dimethoxy-phenyl)-amine;(5-Chloro-2-methoxy-phenyl)-(2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(2,4-Dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;(6,7-Diethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(3-Bromo-phenyl)-(6-fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Chloro-4-fluoro-phenyl)-(6-fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4-fluoro-phenyl)-amine;3-(3-Fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-ol;(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridin-3-yl-amine;3-[6-Ethoxy-3-(3-fluoro-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol;3-[6-Ethoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol;3-[3-(3-Chloro-phenylamino)-6-ethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol;(6-Bromo-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(6-Bromo-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;3-[6-Ethoxy-3-(pyridin-3-ylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol;3-[7-(3-Hydroxy-propoxy)-3-(pyridin-3-ylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(3-Chloro-phenylamino)-7-(3-hydroxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-ethoxy-phenyl)-amine;3-[3-(3-Ethoxy-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;(2-Chloro-pyridin-3-yl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;3-[3-(3-Ethoxy-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;(3-Fluoro-phenyl )-(2H-8-oxa-2,3-diaza-cyclopenta[a]inden-1-yl)-amine;(3-Chloro-4-fluoro-phenyl)-(2H-8-oxa-2,3-diaza-cyclopenta[a]inden-1-yl)-amine;3-[7-Ethoxy-3-(3-fluoro-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[7-Ethoxy-3-(pyridin-3-ylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[7-Ethoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(2-Chloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(2-Fluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(2-Fluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[6-Ethoxy-3-(3-ethoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol;3-[3-(3-Chloro-4-fluoro-phenylamino)-7-(3-hydroxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;1-[3-(2,6-Dichloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[3-(2,6-Difluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[3-(2-Chloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[3-(2-Fluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;3-[3-(3-Fluoro-phenylamino)-7-(3-hydroxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[7-(3-Hydroxy-propoxy)-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(3-Ethoxy-phenylamino)-7-(3-hydroxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;(2,6-Dichloro-benzyl)-[5-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Bromo-phenyl)-(4-ethyl-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Fluoro-phenyl)-(5-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(2-methyl-benzyl)-amine;1-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-2-hydroxy-ethanone;3-[3-(3-Chloro-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-5-yloxy]-propan-1-ol;3-[3-(2-Methyl-benzylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-5-yloxy]-propan-1-ol;3-[3-(2,6-Dichloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(2,6-Difluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(2,6-Dichloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[3-(2-Chloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[3-(2,6-Difluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-3-oxo-propionicacid ethyl ester;1-[6-Ethoxy-3-(3-fluoro-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[6-Ethoxy-3-(pyridin-3-ylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[6-Ethoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[6-Ethoxy-3-(3-ethoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-2-methoxy-ethanone;4-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-4-oxo-butyricacid; Acetic acid2-[3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-2-oxo-ethylester;3-[3-(3-Bromo-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-5-yloxy]-propane-1,2-diol;Methoxy-acetic acid2-[3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-2-oxo-ethylester;(3-Bromo-phenyl)-(4-ethyl-6,7-dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;Butyric acid3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-ylmethylester; Acetic acid3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-ylmethylester; Acetic acid3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-2-ylmethylester;3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazole-2-carboxylicacid 4-fluoro-phenyl ester;5-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-5-oxo-pentanoicacid methylamide;3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazole-1-carboxylicacid (2-morpholin-4-yl-ethyl)-amide;4-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-4-oxo-butyramide;1-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-2-yl]-3-pyrrolidin-1-yl-propane-1,3-dione;(3-Bromo-phenyl)-(6,7-dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-ethoxy-phenyl)-amine;(3-Bromo-phenyl)-(4-ethyl-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Ethoxy-phenyl)-(4-ethyl-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;N-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-5-yl]-acetamide;N3-(3-Fluoro-phenyl)-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazole-3,5-diamine;(2-Chloro-pyridin-3-yl)-(6,7-dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(4-Methoxy-2-methyl-6,9-dihydro-3-oxa-1,6,7-triaza-cyclopenta[b]-as-indacen-8-yl)-(3-methoxy-phenyl)-amine;(2-Bromo-benzyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(5-Bromo-pyridin-2-yl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-isopropoxy-phenyl)-amine;(2,6-Dichloro-benzyl)-(6,7-dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(7-Methoxy-2H-8-oxa-2,3-diaza-cyclopenta[a]inden-1-yl)-phenyl-amine;(3-Fluoro-phenyl)-(4-methoxy-2-methyl-8a,9-dihydro-3-oxa-1,6,7-triaza-cyclopenta[b]-as-indacen-8-yl)-amine;and,3-(3-Fluoro-phenylamino)-6-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-7-ol.43. A compound selected from the group consisting of:3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-benzoicacid methyl ester;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4-fluoro-phenyl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridin-3-yl-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-m-tolyl-amine;(7-Methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-phenyl-amine;(3-Bromo-phenyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;[5-(3-Dimethylamino-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-fluoro-phenyl)-amine;3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-benzamide;N3-(3-Methoxy-phenyl)-2,4-dihydro-indeno[1,2-c]pyrazole-3,6-diamine;N3-(3-Chloro-phenyl)-2,4-dihydro-indeno[1,2-c]pyrazole-3,6-diamine;(3-Bromo-phenyl)-[6-(4-methyl-piperazin-1-yl)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Chloro-phenyl)-[6-(4-methyl-piperazin-1-yl)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Bromo-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;[7-Methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-methoxy-phenyl)-amine;(3-Chloro-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Fluoro-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;[6-(3-Methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-phenyl-amine;(3-Methoxy-phenyl)-[7-methoxy-6-(3-pyrrolidin-1-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;3-[7-Methoxy-6-(3-pyrrolidin-1-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino]-benzoicacid methyl ester;(4-Fluoro-phenyl)-(7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Fluoro-phenyl)-(7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Fluoro-phenyl)-[7-methoxy-6-(3-pyrrolidin-1-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Chloro-4-fluoro-phenyl)-[7-methoxy-6-(3-pyrrolidin-1-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Fluoro-phenyl)-(7-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;[6-(3-Dimethylamino-propoxy)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-fluoro-phenyl)-amine;(3-Chloro-4-fluoro-phenyl)-[6-(3-dimethylamino-propoxy)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Chloro-4-fluoro-phenyl)-(6-fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(2,5-Dimethoxy-phenyl)-(6-fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3,5-Difluoro-phenyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methylsulfanyl-phenyl)-amine;(3-Chloro-phenyl)-{7-methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl}-amine;{7-Methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl}-(3-methoxy-phenyl)-amine;(3-Fluoro-phenyl)-{7-methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl}-amine;(3-Fluoro-phenyl)-[6-(3-imidazol-1-yl-propoxy)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(2-Chloro-benzyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(2,5-Difluoro-phenyl)-(6-fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-m-tolyl-amine;(3-Fluoro-phenyl)-[7-methoxy-6-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;[7-Methoxy-6-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-methoxy-phenyl)-amine;(6,7-Diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;(3-Chloro-4-fluoro-phenyl)-(6,7-diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;(3-Bromo-phenyl)-(6,7-dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;3-[3-(3-Chloro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[3-(3-Chloro-4-fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[3-(3-Fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(3-Chloro-4-fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(3-Chloro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;1-[3-(3-Fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[7-Methoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[3-(3-Chloro-4-fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[7-Methoxy-3-(pyridin-3-ylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[3-(3-Chloro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-fluoro-phenyl)-amine;[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-methoxy-phenyl)-amine;[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-(3-chloro-phenyl)-amine;[6,7-Bis-(3-methoxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-pyridin-3-yl-amine;1-[3-(6-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-phenyl]-ethanol;(2-Chloro-benzyl)-(6,7-diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(2,6-Dichloro-benzyl)-(6,7-diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(7-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-phenyl-amine;1-[3-(7-Methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-phenyl]-ethanol;(2,6-Difluoro-benzyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(2,5-Dichloro-benzyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(7-Fluoro-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(2,4-Dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(2,4-Dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;(6,7-Diethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(3-Bromo-phenyl)-(6-fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(4-fluoro-phenyl)-amine;3-(3-Fluoro-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-ol;(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridin-3-yl-amine;3-[6-Ethoxy-3-(3-fluoro-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol;3-[6-Ethoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol;3-[3-(3-Chloro-phenylamino)-6-ethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-propan-1-ol;(6-Bromo-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(6-Bromo-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-methoxy-phenyl)-amine;3-[7-(3-Hydroxy-propoxy)-3-(pyridin-3-ylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(3-Chloro-phenylamino)-7-(3-hydroxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-ethoxy-phenyl)-amine;3-[3-(3-Ethoxy-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;(2-Chloro-pyridin-3-yl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;3-[3-(3-Ethoxy-phenylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;(3-Fluoro-phenyl)-(2H-8-oxa-2,3-diaza-cyclopenta[a]inden-1-yl)-amine;(3-Chloro-4-fluoro-phenyl)-(2H-8-oxa-2,3-diaza-cyclopenta[a]inden-1-yl)-amine;3-[7-Ethoxy-3-(3-fluoro-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[7-Ethoxy-3-(pyridin-3-ylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[7-Ethoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(2-Chloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(2-Fluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(2-Fluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[3-(3-Chloro-4-fluoro-phenylamino)-7-(3-hydroxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;1-[3-(2,6-Dichloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[3-(2,6-Difluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[3-(2-Chloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[3-(2-Fluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;3-[3-(3-Fluoro-phenylamino)-7-(3-hydroxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[7-(3-Hydroxy-propoxy)-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(3-Ethoxy-phenylamino)-7-(3-hydroxy-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;(2,6-Dichloro-benzyl)-[5-(3-morpholin-4-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine;(3-Fluoro-phenyl)-(5-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6-Fluoro-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(2-methyl-benzyl)-amine;3-[3-(2-Methyl-benzylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-5-yloxy]-propan-1-ol;3-[3-(2,6-Dichloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(2,6-Difluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propan-1-ol;3-[3-(2,6-Dichloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[3-(2-Chloro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;3-[3-(2,6-Difluoro-benzylamino)-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-6-yloxy]-propane-1,2-diol;1-[6-Ethoxy-3-(3-fluoro-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[6-Ethoxy-3-(pyridin-3-ylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[6-Ethoxy-3-(3-methoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[6-Ethoxy-3-(3-ethoxy-phenylamino)-2,4-dihydro-indeno[1,2-c]pyrazol-7-yloxy]-3-pyrrolidin-1-yl-propan-2-ol;1-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-2-methoxy-ethanone;Acetic acid2-[3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-2-oxo-ethylester; Methoxy-acetic acid2-[3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-2-oxo-ethylester; Acetic acid3-(3-fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-ylmethyl ester;4-[3-(3-Fluoro-phenylamino)-6,7-dimethoxy-4H-indeno[1,2-c]pyrazol-1-yl]-4-oxo-butyramide;(3-Bromo-phenyl)-(6,7-dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Dimethoxy-4-methyl-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-ethoxy-phenyl)-amine;(3-Bromo-phenyl)-(4-ethyl-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(3-Ethoxy-phenyl)-(4-ethyl-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;N3-(3-Fluoro-phenyl)-6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazole-3,5-diamine;(4-Methoxy-2-methyl-6,9-dihydro-3-oxa-1,6,7-triaza-cyclopenta[b]-as-indacen-8-yl)-(3-methoxy-phenyl)-amine;(2-Bromo-benzyl)-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-amine;(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-isopropoxy-phenyl)-amine;(6,7-Diethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine;(7-Methoxy-2H-8-oxa-2,3-diaza-cyclopenta[a]inden-1-yl )-phenyl-amine;(3-Fluoro-phenyl)-(4-methoxy-2-methyl-8a,9-dihydro-3-oxa-1,6,7-triaza-cyclopenta[b]-as-indacen-8-yl)-amine;and3-(3-Fluoro-phenylamino)-6-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-7-ol.44. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of claims 1, 7, 20, 22, 24, 26, 28-30,32, 34, and 36-43.
 45. A pharmaceutical composition made by mixing acompound of claims 1, 7, 20, 22, 24, 26, 28-30, 32, 34, and 36-43 and apharmaceutically acceptable carrier.
 46. A process for making apharmaceutical composition comprising mixing a compound of claims 1, 7,20, 22, 24, 26, 28-30, 32, 34, and 36-43 and a pharmaceuticallyacceptable carrier.
 47. A method of treating a disorder related to PDGFreceptor or a cell proliferative disorder in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of the compound of claims 1, 7, 20, 22, 24, 26, 28-30, 32, 34,and 36-43.
 48. A method of treating a cell proliferative disorder or adisorder related to PDGF receptor in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of the composition of claim
 44. 49. The method of claim 48wherein said cell proliferative disorder is a neoplastic disorder. 50.The method of claim 49 wherein said the neoplastic disorder is a cancerselected from the group consisting of a glioma cancer, a lung cancer, abreast cancer, a colorectal cancer, a prostate cancer, a gastric cancer,an esophageal cancer, a colon cancer, a pancreatic cancer, an ovariancancer, a melanoma, a myelodysplasia, a multiple myeloma, a lymphoma,and a leukemia.
 51. The method of claim 50 wherein said leukemia isselected from chronic myelogenous leukemia (CML); acute lymphocyticleukemia (ALL); chronic neutrophilic leukemia (CNL); acuteundifferentiated leukemia (AUL); and acute myelogenous leukemia (AML).52. The method of claim 48 wherein said cell proliferative disorder isnot a neoplastic disorder.
 53. The method of claim 52 wherein said cellproliferative disorder is selected from atherosclerosis,transplantation-induced vasculopathies, neointima formation, lungfibrosis, macular degeneration, restenosis, pulmonary fibrosis,glomerulonephritis, glomerulosclerosis, congenital multicystic renaldysplasia, kidney fibrosis, diabetic retinopathy and rheumatoidarthritis.
 54. A method for treating a cell proliferative disorder or adisorder related to PDGF receptor in a subject in need thereofcomprising administration of a therapeutically effective amount of acompound of claims 1, 7, 20, 22, 24, 26, 28-30, 32, 34, and 36-43 incombination with one or more therapies choosing from the groupconsisting of a chemotherapy, a radiation therapy, a gene therapy, andan immunotherapy.
 55. A method of treating a cell proliferative disorderor a disorder related to PDGF-R in a subject in need thereof comprisingthe controlled delivery, by release from an intraluminal medical device,of a therapeutically effective amount of a compound of claims 1, 7, 20,22, 24, 26, 28-30, 32, 34, and 36-43.
 56. The method of claim 55 whereinsaid cell proliferative disorder or a disorder related to PDGF-R isrestenosis, intimal hyperplasia, atherosclerosis or inflammation, invessel walls.
 57. A drug delivery device comprising an intraluminalmedical device, and a therapeutically effective amount of a compound ofclaims 1, 7, 20, 22, 24, 26, 28-30, 32, 34, and 36-43.
 58. The drugdelivery device of claim 57, wherein the intraluminal medical device isa stent.
 59. A method of treating a cell proliferative disorder or adisorder related to PDGF receptor in a subject in need thereof,comprising administering to the subject a therapeutic effective amountof a compound of claims 1, 7, 20, 22, 24, 26, 28-30, 32, 34, and 36-43conjugated to a targeting agent.
 60. The method of claim 59, whereinsaid cell proliferative disorder is a neoplastic disorder selected froma glioma cancer, a lung cancer, a breast cancer, a colorectal cancer, aprostate cancer, a gastric cancer, an esophageal cancer, a colon cancer,a pancreatic cancer, an ovarian cancer, a melanoma, a myelodysplasia, amultiple myeloma, a leukemia and a lymphoma.
 61. A pharmaceuticalcomposition comprising a compound of claims 1, 7, 20, 22, 24, 26, 28-30,32, 34, and 36-43 conjugated to a targeting agent and a pharmaceuticallyacceptable carrier.
 62. A pharmaceutical composition made by mixing acompound of claims 1, 7, 20, 22, 24, 26, 28-30, 32, 34, and 36-43conjugated to a targeting agent and a pharmaceutically acceptablecarrier.
 63. A process for making a pharmaceutical compositioncomprising mixing a compound of claims 1, 7, 20, 22, 24, 26, 28-30, 32,34, and 36-43 conjugated to a targeting agent and a pharmaceuticallyacceptable carrier.
 64. A method of identifying novel PDGF-R kinaseinhibitors comprising the steps of: (a) determining a three-dimensionalstructure of the compound of Fomula I or II in the absence or presenceof a polypeptide comprising the PDGF-R kinase catalytic domain; (b)analyzing the three-dimensional structure for the compound alone or forthe intermolecular interaction between said compound and PDGF-R; (c)selecting a compound that mimics the structure for the compound alone orincorporates the predictive interaction; (d) synthesizing said designedcompound; and (e) determining the ability of the molecule to bind andinhibit PDGF-R kinase activity.
 65. A method of identifying novel c-Ablkinase inhibitors comprising the steps of: (a) determining athree-dimensional structure of the compound of Fomula I or II in theabsence or presence of a polypeptide comprising the c-Abl kinasecatalytic domain; (b) analyzing the three-dimensional structure for thecompound alone or for the intermolecular interaction between saidcompound and c-Abl; (c) selecting a compound that mimics the structurefor the compound alone or incorporates the predictive interaction; (d)synthesizing said designed compound; and (e) determining the ability ofthe molecule to bind and inhibit c-Abl kinase activity.
 66. A method forreducing or inhibiting the PDGF-R kinase activity in a cell comprisingthe step of contacting the cell with a compound of Formula (I) or (II).67. A method for reducing or inhibiting the PDGF-R kinase activity in asubject coprising the step of administering to the subject a compound ofFormula (I) or (II).
 68. A method for reducing or inhibiting the c-Ablkinase activity in a cell comprising the step of contacting the cellwith a compound of Formula (I) or (II).
 69. A method for reducing orinhibiting the c-Abl kinase activity in a subject comprising the step ofadministering to the subject a compound of Formula (I) or (II).
 70. Amethod of inhibiting cell proliferation in a cell comprising the step ofcontacting the cell with a compound of Formula (I) or (II).
 71. Aprocess for the preparation of a compound of Formula (I):

wherein n is an integer from 1 to 4; R¹ is selected from the groupconsisting of hydrogen, lower alkyl, —OH, alkoxy, -oxo, —NH₂, —NH(alkyl)and —N(alkyl)₂;

is selected from the group consisting of an aryl, a five to six memberedmonocyclic heteroaryl, a nine to ten membered benzo-fused heteroaryl, anine to ten membered benzo-fused heterocycloalkyl group, and a nine toten membered benzo-fused cycloalkyl group; wherein the benzo-fusedheteroaryl, benzo-fused heterocycloalkyl or benzo-fused cycloalkyl groupis attached to the molecule such that the phenyl ring is bound directlyto the

portion of the molecule; p is an integer from 0 to 2; R² is selectedfrom the group consisting of

and —X-A¹-Y-A²; wherein, X and Y are each independently absent orselected from the group consisting of —O—, —NH—, —N(alkyl)—, —S—, —SO—,—SO₂—, —OC(═O), —C(═O)O—, —NHC(═O)—, —N(alkyl)C(═O)—, —C(═O)NH—,—C(═O)N(alkyl)—, —OC(═O)O—, —NHC(═O)O—, —OC(═O)NH—, —N(alkyl)C(═O)O—,—OC(═O)N(alkyl)-, —NHC(═O)NH— —NHC(═O)N(alkyl)-, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)N(alkyl)-, —NHSO₂—, —SO₂NH—, —N(alkyl)SO₂— and—SO₂N(alkyl)-; A¹ is absent or selected from alkyl or alkenyl; A² isselected from alkyl, alkenyl, or H; wherein, when A¹ or A² is alkyl oralkenyl, the alkyl or alkenyl group may be optionally substituted withone or more groups independently selected from halogen, cyano, hydroxy,alkoxy, thio, halogenated alkoxy, —OC(═O)alkyl, —OC(═O)Oalkyl, amino,alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, dialkylamino,—NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)NH₂,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(=O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂;

is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl; wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, is optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, amino, thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy,halogenated alkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, ordialkylamino, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(=O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂; q is an integer from 0 to 4; R³ is selected from thegroup consisting of halogen, hydroxy, amino, thio, nitro, cyano, alkyl,halogenated alkyl, alkoxy, halogenated alkyloxy, alkylamino,—NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, or dialkylamino, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —OC(═O)NHalkyl, —NHC(═O)Oalkyl,—N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl, —N(alkyl)SO₂alkyl, thioalkyl,halogenated thioalkyl, —SO₂alkyl, halogenated —SO₂alkyl,—NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ and —OC(═O)N(alkyl)₂;provided that the sum of p and q is an integer from 0 to 4; L¹ is absentor selected from the group consisting of alkyl;

is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl; or an optical isomer, enantiomer,diastereomer, racemate, or pharmaceutically acceptable salt thereof;comprising

reacting a compound of formula (S3) with hydrazine, to yield thecorresponding compound of formula (I).
 72. The process of claim 71,further comprising

reacting a compound of formula (S5) with a compound of formula (S6), inan aprotic solvent, to yield the corresponding compound of formula (S3).73. The process of claim 72, further comprising

reacting a compound of formula (S1) with 1,1′-thiocarbonylimidazole, inthe presence of abase, in an aprotic solvent, to yield the correspondingcompound of formula (S5).
 74. A process for the preparation of acompound of formula (S5)

wherein n is an integer from 1 to 4; R¹ is selected from the groupconsisting of hydrogen, lower alkyl, —OH, alkoxy, -oxo, —NH₂, —NH(alkyl)and —N(alkyl)₂;

is selected from the group consisting of an aryl, a five to six memberedmonocyclic heteroaryl, a nine to ten membered benzo-fused heteroaryl, anine to ten membered benzo-fused heterocycloalkyl group, and a nine toten membered benzo-fused cycloalkyl group; wherein the benzo-fusedheteroaryl, benzo-fused heterocycloalkyl or benzo-fused cycloalkyl groupis attached to the molecule such that the phenyl ring is bound directlyto the

portion of the molecule; p is an integer from 0 to 2; R² is selectedfrom the group consisting of

and —X-A¹-Y-A²; wherein, X and Y are each independently absent orselected from the group consisting of —O—, —NH—, —N(alkyl)-, —S—, —SO—,—SO₂—, —OC(═O), —C(═O)O—, —NHC(═O)—, —N(alkyl)C(═O)—, —C(═O)NH—,—C(═O)N(alkyl)—, —OC(═O)O—, —NHC(═O)O—, —OC(═O)NH—, —N(alkyl)C(═O)O—,—OC(═O)N(alkyl)-, —NHC(═O)NH— —NHC(═O)N(alkyl)-, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)N(alkyl)-, —NHSO₂—, —SO₂NH—, —N(alkyl)SO₂— and—SO₂N(alkyl)-; A¹ is absent or selected from alkyl or alkenyl; A² isselected from alkyl, alkenyl, or H; wherein, when A¹ or A² is alkyl oralkenyl, the alkyl or alkenyl group may be optionally substituted withone or more groups independently selected from halogen, cyano, hydroxy,alkoxy, thio, halogenated alkoxy, —OC(═O)alkyl, —OC(═O)Oalkyl, amino,alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, dialkylamino,—NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)NH₂,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂;

is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl; wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, is optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, amino, thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy,halogenated alkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, ordialkylamino, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂; q is an integer from 0 to 4; R³ is selected from thegroup consisting of halogen, hydroxy, amino, thio, nitro, cyano, alkyl,halogenated alkyl, alkoxy, halogenated alkyloxy, alkylamino,—NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, or dialkylamino, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —OC(═O)NHalkyl, —NHC(═O)Oalkyl,—N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl, —N(alkyl)SO₂alkyl, thioalkyl,halogenated thioalkyl, —SO₂alkyl, halogenated —SO₂alkyl,—NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ and —OC(═O)N(alkyl)₂;provided that the sum of p and q is an integer from 0 to 4; or anoptical isomer, enantiomer, diastereomer, racemate, or pharmaceuticallyacceptable salt thereof; comprising

reacting a compound of formula (Si) with 1,1′-thiocarbonylimidazole, inthe presence of abase, in an aprotic solvent, to yield the correspondingcompound of formula (S5).
 75. A process for the preparation of acompound of formula (S3)

wherein, n is an integer from 1 to 4; R¹ is selected from the groupconsisting of hydrogen, lower alkyl, —OH, alkoxy, -oxo, —NH₂, —NH(alkyl)and —N(alkyl)₂;

is selected from the group consisting of an aryl, a five to six memberedmonocyclic heteroaryl, a nine to ten membered benzo-fused heteroaryl, anine to ten membered benzo-fused heterocycloalkyl group, and a nine toten membered benzo-fused cycloalkyl group; wherein the benzo-fusedheteroaryl, benzo-fused heterocycloalkyl or benzo-fused cycloalkyl groupis attached to the molecule such that the phenyl ring is bound directlyto the

portion of the molecule; p is an integer from 0 to 2; R² is selectedfrom the group consisting of

and —X-A¹-Y-A²; wherein, X and Y are each independently absent orselected from the group consisting of —O—, —NH—, —N(alkyl)-, —S—, —SO—,—SO₂—, —OC(═O), —C(═O)O—, —NHC(═O)—, —N(alkyl)C(═O)—, —C(═O)NH—,—C(═O)N(alkyl)-, —OC(═O)O—, —NHC(═O)O—, —OC(═O)NH—, —N(alkyl)C(═O)O—,—OC(═O)N(alkyl)-, —NHC(═O)NH—, —NHC(═O)N(alkyl)-, —N(alkyl)C(═O)NH—,—N(alkyl)C(═O)N(alkyl)-, —NHSO₂—, —SO₂NH—, —N(alkyl)SO₂— and—SO₂N(alkyl)-; A¹ is absent or selected from alkyl or alkenyl; A² isselected from alkyl, alkenyl, or H; wherein, when A¹ or A² is alkyl oralkenyl, the alkyl or alkenyl group may be optionally substituted withone or more groups independently selected from halogen, cyano, hydroxy,alkoxy, thio, halogenated alkoxy, —OC(═O)alkyl, —OC(═O)Oalkyl, amino,alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, dialkylamino,—NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)NH₂,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂;

is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl; wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, is optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, amino, thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy,halogenated alkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, ordialkylamino, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl,—OC(═O)NHalkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, thioalkyl, halogenated thioalkyl, —SO₂alkyl,halogenated —SO₂alkyl, —NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or—OC(═O)N(alkyl)₂; q is an integer from 0 to 4; R³ is selected from thegroup consisting of halogen, hydroxy, amino, thio, nitro, cyano, alkyl,halogenated alkyl, alkoxy, halogenated alkyloxy, alkylamino,—NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, or dialkylamino, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —OC(═O)NHalkyl, —NHC(═O)Oalkyl,—N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl, —N(alkyl)SO₂alkyl, thioalkyl,halogenated thioalkyl, —SO₂alkyl, halogenated —SO₂alkyl,—NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ and —OC(═O)N(alkyl)₂;provided that the sum of p and q is an integer from 0 to 4; L¹ is absentor selected from the group consisting of alkyl;

is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl; or an optical isomer, enantiomer,diastereomer, racemate, or pharmaceutically acceptable salt thereof;comprising

reacting a compound of formula (S5) with a compound of formula (S6), inan aprotic solvent, to yield the corresponding compound of formula (S3).76. A process for the preparation of a compound of Formula (IIa):

wherein:

is selected from the group consisting of Formulae A-1, A-2 and A-3:

wherein Formula A-1 is attached on the b¹ side of Formula A-1 to the L²ring of formula (II) and optionally substituted with one substituentselected from the group consisting of Formulae A-1-a, A-1-b and A-1-c:

wherein Formula A-1-a is attached on the a¹ side to adjacent carbons onthe d¹ or d² side of Formula A-1;

wherein Formula A-1-b is attached on the a² side to adjacent carbons onthe d¹ or d² side of Formula A-1; and

wherein Formula A-1-c is attached on the a⁶ side to adjacent carbons onthe d¹ or d² side of Formula A-1; wherein R⁸ is H or alkyl;

wherein Formula A-2 is attached on the b² side of Formula A-2 to the L²ring of formula (II), and A¹, A², A³, A⁴ are (i) —N—; or (ii) —C—substituted with H or alkoxy, wherein the alkoxy may be optionallyfurther substituted with alkoxy on a terminal carbon or up to 3 halogenatoms on a terminal carbon; provided that at least one and no more thantwo of A¹, A², A³, A⁴ are —N—; and

wherein Formula A-3 is attached on the b³ side of Formula A-3 to the L²ring of formula (II), and B¹, B² and B³are independently (i) —CH—optionally substituted with alkyl, aryl, alkoxy, or halogen, (ii) —S—;(iii) —O—; or (iv) —N—; provided that no more than one of B¹, B² or B³is —S— or —O—, and, provided that when one of B¹, B² or B³ is —S— or—O—, then the adjacent ring members are not —S— or —O—; R⁹ isindependently selected from the group consisting of: alkoxy, alkyl,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkyl,halogenated alkyloxy, halogenated —SO₂alkyl, halogenated thioalkyl,hydroxy, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—SO₂alkyl, thio and thioalkyl; L² is a linking group selected from thegroup consisting of: —(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—,—O—, —O(CH₂)₁₋₄—, —OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-,—N(COalkyl)-, —N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and—N(SO₂aryl)-; wherein R¹⁰⁰ is one or two substituents independentlyselected from: alkyl, hydroxy, aryl, alkoxy, oxo, —NH₂, —NH(alkyl)—N(alkyl)₂, ═N(OH) or —NH₂OH; provided that when L² is —OCH(R¹⁰⁰)—, R¹⁰⁰is alkoxy, and

is phenyl, R⁵ is not —C(═O)NH—NH₂; R¹⁰ is independently selected fromthe group consisting of

and —X¹-A²⁰-Y-A²¹; wherein X¹ and Y¹ are each independently absent orselected from the group consisting of: -(alkyl)C(═O)N(alkyl)-,—C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)═,═N(alkyl)C(═O)NH—, —N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—,—NHC(═O)N(alkyl)-, —NHC(═O)NH, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O),—OC(═O)N(alkyl)-, —OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—,—SO₂N(alkyl)-, and —SO₂NH—; A²⁰ is absent or selected from alkyl oralkenyl; and A²¹ is selected from alkyl, alkenyl, or H; wherein when A²⁰or A²¹ is alkyl or alkenyl, the alkyl or alkenyl may be optionallysubstituted with one or more groups independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated —SO₂alkyl, halogenated thioalkyl, hydroxy,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl;

is selected from the group consisting of aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, nine to tenmembered benzo-fused cycloalkyl, and nine to ten membered benzo-fusedheterocycloalkyl; wherein, the aryl, cycloalkyl, partially unsaturatedcarbocycle, heteroaryl, heterocycloalkyl, benzo-fused cycloalkyl, orbenzo-fused heterocycloalkyl, are optionally substituted with one ormore substituents independently selected from halogen, hydroxy, amino,thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy, halogenatedalkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, or dialkylamino,—NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —OC(═O)NHalkyl,—NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl, —N(alkyl)SO₂alkyl,thioalkyl, halogenated thioalkyl, —SO₂alkyl, halogenated —SO₂alkyl,—NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or —OC(═O)N(alkyl)₂; s is aninteger from 0 to 2; m is an integer from 0 to 4; provided that when

is not substituted with Formulae A-1-a, A-1-b or A-1-c, the sum of m ands is an integer from 0 to 4, and when

is substituted with one of Formulae A-1-a, A-1-b, or A-1-c, the sum of mand s is an integer from 0 to 2; L³ is absent or is a linking groupselected from the group consisting of alkyidiyl, carbonyl or —SO₂—;

is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, aralkyl, a heteroaryl, aheterocycloalkyl, a nine to ten membered benzo-fused cycloalkyl, a nineto ten membered benzo-fused heteroaryl, and a nine to ten memberedbenzo-fused heterocycloalkyl; r is an integer from 0 to 4; and R⁵ isindependently selected from the group consisting of: alkyl, alkyl amino,alkyloxy, amino, —C(═O)NH₂, —C(═O)Oalkyl, —C(═O)OH, —CH₂OH, cyano,dialkylamino, halogen, halogenated alkyl, halogenated alkyloxy,halogenated SO₂-alkyl, halogenated thioalkyl, hydroxy, hydroxy alkyl,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —SO₂alkyl,—SO₂NH₂, thio, thioalkyl,

and —V—B¹⁰—W—B²⁰; wherein, V and W are each independently absent orselected from the group consisting of: —C(═O), —C(═O)N(alkyl)-,—C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—,—N(alkyl)C(═O)N(alkyl)-, —N(alkyl)C(═O)NH—, —N(alkyl)C(═O)O—,—N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-, —NHC(═O)NH—,—NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-, —OC(═O)NH—,—OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)- and —SO₂NH—; B¹⁰ is absent orselected from alkyl or alkenyl; B²⁰ is absent or selected from alkyl,alkenyl, or H; wherein, when B¹⁰ or B²⁰ is alkyl or alkenyl, the alkylor alkenyl group may be optionally substituted with one or more groupsindependently selected from: alkoxy, alkylamino, amino, cyano,dialkylamino, halogen, halogenated alkoxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl; and

is selected from the group consisting of: an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl, wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, is optionally substitutedwith one or more substituents independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated alkyl, halogenated —SO₂alkyl, halogenated thioalkyl,heteroaryl, hydroxy, hydroxy alkyl, —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —SO₂alkyl, thio or thioalkyl; or an optical isomer,enantiomer, diastereomer, racemate, or pharmaceutically acceptable saltthereof; comprising: reacting a compound of formula (T3) with hydrazine,

to yield the corresponding compound of formula (IIa).
 77. The process ofclaim 76, further comprising

reacting a compound of formula (T5) with a compound of formula (T6), inan aprotic solvent, to yield the corresponding compound of formula (T3).78. The process of claim 77, further comprising

reacting a compound of formula (T1) with 1,1′-thiocarbonyldiimidazole,in the presence of a base, in an aprotic solvent, to yield thecorresponding compound of formula (T5).
 79. A process for thepreparation of a compound of formula (T5)

wherein

is selected from the group consisting of Formulae A-1, A-2 and A-3:

wherein Formula A-1 is attached on the b¹ side of Formula A-1 to the L²ring of formula (II) and optionally substituted with one substituentselected from the group consisting of Formulae A-1-a, A-1-b and A-1-c:

wherein Formula A-1-a is attached on the a¹ side to adjacent carbons onthe d¹ or d² side of Formula A-1;

wherein Formula A-1-b is attached on the a² side to adjacent carbons onthe d¹ or d² side of Formula A-1; and

wherein Formula A-1-c is attached on the a⁶ side to adjacent carbons onthe d¹ or d² side of Formula A-1; wherein R⁸ is H or alkyl;

wherein Formula A-2 is attached on the b² side of Formula A-2 to the L²ring of formula (II), and A¹, A², A³, A⁴ are (i) —N—; or (ii) —C—substituted with H or alkoxy, wherein the alkoxy may be optionallyfurther substituted with alkoxy on a terminal carbon or up to 3 halogenatoms on a terminal carbon; provided that at least one and no more thantwo of A¹, A², A³, A⁴ are —N—; and

wherein Formula A-3 is attached on the b³ side of Formula A-3 to the L²ring of formula (II), and B¹, B² and B³are independently (i) —CH—optionally substituted with alkyl, aryl, alkoxy, or halogen, (ii) —S—;(iii) —O—; or (iv) —N—; provided that no more than one of B¹, B² or B³is —S— or —O—, and, provided that when one of B¹, B² or B³ is —S— or—O—, then the adjacent ring members are not —S— or —O—; R⁹ isindependently selected from the group consisting of: alkoxy, alkyl,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkyl,halogenated alkyloxy, halogenated —SO₂alkyl, halogenated thioalkyl,hydroxy, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—SO₂alkyl, thio and thioalkyl; L² is a linking group selected from thegroup consisting of: —(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—,—O—, —O(CH₂)₁₋₄—, —OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-,—N(COalkyl)-, —N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and—N(SO₂aryl)-; wherein R¹⁰⁰ is selected from: alkyl, hydroxy, aryl,alkoxy, oxo, —NH₂, —NH(alkyl) —N(alkyl)₂, ═N(OH) or —NH₂OH; R¹⁰ isindependently selected from the group consisting of

and —X¹-A²⁰-Y¹-A²¹; wherein X¹ and Y¹ are each independently absent orselected from the group consisting of: -(alkyl)C(═O)N(alkyl)-,—C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—,—N(alkyl)C(═O)NH—, —N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—,—NHC(═O)N(alkyl)-, —NHC(═O)NH, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O),—OC(═O)N(alkyl)-, —OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—,—SO₂N(alkyl)-, and —SO₂NH—; A²⁰ is absent or selected from alkyl oralkenyl; and A²¹ is selected from alkyl, alkenyl, or H; wherein when A²⁰or A²¹ is alkyl or alkenyl, the alkyl or alkenyl may be optionallysubstituted with one or more groups independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated —SO₂alkyl, halogenated thioalkyl, hydroxy,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl;

is selected from the group consisting of aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, nine to tenmembered benzo-fused cycloalkyl, and nine to ten membered benzo-fusedheterocycloalkyl; wherein, the aryl, cycloalkyl, partially unsaturatedcarbocycle, heteroaryl, heterocycloalkyl, benzo-fused cycloalkyl, orbenzo-fused heterocycloalkyl, are optionally substituted with one ormore substituents independently selected from halogen, hydroxy, amino,thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy, halogenatedalkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, or dialkylamino,—NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —OC(═O)NHalkyl,—NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl, —N(alkyl)SO₂alkyl,thioalkyl, halogenated thioalkyl, —SO₂alkyl, halogenated —SO₂alkyl,—NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or —OC(═O)N(alkyl)₂; s is aninteger from 0 to 2; m is an integer from 0 to 4; provided that when

is not substituted with Formulae A-1-a, A-1-b or A-1-c, the sum of m ands is an integer from 0 to 4, and when

is substituted with one of Formulae A-1-a, A-1-b, or A-1-c, the sum of mand s is an integer from 0 to 2; or an optical isomer, enantiomer,diastereomer, racemate, or pharmaceutically acceptable salt thereof;comprising

reacting a compound of formula (T1) with 1,1′-thiocarbonyldiimidazole,in the presence of a base, in an aprotic solvent, to yield thecorresponding compound of formula (T5).
 80. A process for thepreparation of a compound of formula (T3)

wherein:

is selected from the group consisting of Formulae A-1, A-2 and A-3:

wherein Formula A-1 is attached on the b¹ side of Formula A-1 to the L²ring of formula (II) and optionally substituted with one substituentselected from the group consisting of Formulae A-1-a, A-1-b and A-1-c:

wherein Formula A-1-a is attached on the a¹ side to adjacent carbons onthe d¹ or d² side of Formula A-1;

wherein Formula A-1-b is attached on the a² side to adjacent carbons onthe d¹ or d² side of Formula A-1; and

wherein Formula A-1-c is attached on the a⁶ side to adjacent carbons onthe d¹ or d² side of Formula A-1; wherein R⁸ is H or alkyl;

wherein Formula A-2 is attached on the b² side of Formula A-2 to the L²ring of formula (II), and A¹, A², A³, A⁴ are (i) —N—; or (ii) —C—substituted with H or alkoxy, wherein the alkoxy may be optionallyfurther substituted with alkoxy on a terminal carbon or up to 3 halogenatoms on a terminal carbon; provided that at least one and no more thantwo of A¹, A², A³, A⁴ are —N—; and

wherein Formula A-3 is attached on the b³ side of Formula A-3 to the L²ring of formula (II), and B¹, B² and B³ are independently (i) —CH—optionally substituted with alkyl, aryl, alkoxy, or halogen, (ii) —S—;(iii) —O—; or (iv) —N—; provided that no more than one of B¹, B² or B³is —S— or —O—, and, provided that when one of B¹, B² or B³ is —S— or—O—, then the adjacent ring members are not —S— or —O—; R⁹ isindependently selected from the group consisting of: alkoxy, alkyl,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkyl,halogenated alkyloxy, halogenated —SO₂alkyl, halogenated thioalkyl,hydroxy, —N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHS₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—SO₂alkyl, thio and thioalkyl; L² is a linking group selected from thegroup consisting of: —(CH₂)₁₋₄—, —CH(R¹⁰⁰)—, —C(═R¹⁰⁰)—, —C(R¹⁰⁰)₂—,—O—, —O(CH₂)₁₋₄—, —OCH(R¹⁰⁰)—, —OC(R¹⁰⁰)₂—, —S—, —NH—, —N(lower alkyl)-,-N(COalkyl)-, —N(aryl)-, —N(CO₂alkyl)-, —N(CONHalkyl)-, —N(SO₂alkyl) and—N(SO₂aryl)-; wherein R¹⁰⁰ is selected from: alkyl, hydroxy, aryl,alkoxy, oxo, —NH₂, —NH(alkyl) —N(alkyl)₂, ═N(OH) or —NH₂OH; R¹⁰ isindependently selected from the group consisting of

and —X¹-A²⁰-Y¹-A²¹; wherein X¹ and Y¹ are each independently absent orselected from the group consisting of: -(alkyl)C(═O)N(alkyl)-,—C(═O)N(alkyl)-, —C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—,−N(alkyl)C(═O)NH—, —N(alkyl)C(═O)O—, —N(alkyl)SO₂—, —NH—, —NHC(═O)—,—NHC(═O)N(alkyl)-, —NHC(═O)NH, —NHC(═O)O—, —NHSO₂—, —O—, —OC(═O),—OC(═O)N(alkyl)-, —OC(═O)NH—, —OC(═O)O—, —S—, —SO—, —SO₂—,—SO₂N(alkyl)-, and —SO₂NH—; A²⁰ is absent or selected from alkyl oralkenyl; and A²¹ is selected from alkyl, alkenyl, or H; wherein when A²⁰or A²¹ is alkyl or alkenyl, the alkyl or alkenyl may be optionallysubstituted with one or more groups independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated —SO₂alkyl, halogenated thioalkyl, hydroxy,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂,—N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl,—NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl,—NHC(═O)Oalkyl, —NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl;

is selected from the group consisting of aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, nine to tenmembered benzo-fused cycloalkyl, and nine to ten membered benzo-fusedheterocycloalkyl; wherein, the aryl, cycloalkyl, partially unsaturatedcarbocycle, heteroaryl, heterocycloalkyl, benzo-fused cycloalkyl, orbenzo-fused heterocycloalkyl, are optionally substituted with one ormore substituents independently selected from halogen, hydroxy, amino,thio, nitro, cyano, alkyl, halogenated alkyl, alkoxy, halogenatedalkoxy, alkylamino, —NHC(═O)alkyl, —N(alkyl)C(═O)alkyl, or dialkylamino,—NHC(═O)NH₂, —NHC(═O)NHalkyl, —N(alkyl)C(═O)NHalkyl, —OC(═O)NHalkyl,—NHC(═O)Oalkyl, —N(alkyl)C(═O)Oalkyl, —NHSO₂alkyl, —N(alkyl)SO₂alkyl,thioalkyl, halogenated thioalkyl, —SO₂alkyl, halogenated —SO₂alkyl,—NHC(═O)N(alkyl)₂, —N(alkyl)C(═O)N(alkyl)₂ or —OC(═O)N(alkyl)₂; s is aninteger from 0 to 2; m is an integer from 0 to 4; provided that when

is not substituted with Formulae A-1-a, A-1-b or A-1-c, the sum of m ands is an integer from 0 to 4, and when

is substituted with one of Formulae A-1-a, A-1-b, or A-1-c, the sum of mand s is an integer from 0 to 2; L³ is absent or is a linking groupselected from the group consisting of alkyldiyl, carbonyl or —SO₂—;

is selected from the group consisting of an aryl, a cycloalkyl, apartially unsaturated carbocycle, aralkyl, a heteroaryl, aheterocycloalkyl, a nine to ten membered benzo-fused cycloalkyl, a nineto ten membered benzo-fused heteroaryl, and a nine to ten memberedbenzo-fused heterocycloalkyl; r is an integer from 0 to 4; and R⁵ isindependently selected from the group consisting of: alkyl, alkyl amino,alkyloxy, amino, —C(═O)NH₂, —C(═O)Oalkyl, —C(═O)OH, —CH₂OH, cyano,dialkylamino, halogen, halogenated alkyl, halogenated alkyloxy,halogenated SO₂-alkyl, halogenated thioalkyl, hydroxy, hydroxy alkyl,—N(alkyl)C(═O)alkyl, —N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl, —SO₂alkyl,—SO₂NH₂, thio, thioalkyl,

and —V—B¹⁰—W—B²⁰; wherein, V and W are each independently absent orselected from the group consisting of: —C(═O), —C(═O)N(alkyl)-,—C(═O)NH—, —C(═O)O—, —N(alkyl)-, —N(alkyl)C(═O)—,—N(alkyl)C(═O)N(alkyl)-, —N(alkyl)C(═O)NH—, —N(alkyl)C(═O)O—,—N(alkyl)SO₂—, —NH—, —NHC(═O)—, —NHC(═O)N(alkyl)-, —NHC(═O)NH—,—NHC(═O)O—, —NHSO₂—, —O—, —OC(═O), —OC(═O)N(alkyl)-, —OC(═O)NH—,—OC(═O)O—, —S—, —SO—, —SO₂—, —SO₂N(alkyl)- and —SO₂NH—; B¹⁰ is absent orselected from alkyl or alkenyl; B²⁰ is absent or selected from alkyl,alkenyl, or H; wherein, when B¹⁰ or B²⁰ is alkyl or alkenyl, the alkylor alkenyl group may be optionally substituted with one or more groupsindependently selected from: alkoxy, alkylamino, amino, cyano,dialkylamino, halogen, halogenated alkoxy, halogenated —SO₂alkyl,halogenated thioalkyl, hydroxy —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NH₂, —N(alkyl)C(═O)NHalkyl,—N(alkyl)C(═O)Oalkyl, —N(alkyl)SO₂alkyl, —NHC(═O)alkyl,—NHC(═O)N(alkyl)₂, —NHC(═O)NH₂, —NHC(═O)NHalkyl, —NHC(═O)Oalkyl,—NHSO₂alkyl, —OC(═O)alkyl, —OC(═O)N(alkyl)₂, —OC(═O)NHalkyl,—OC(═O)Oalkyl, —SO₂alkyl, thio or thioalkyl; and

is selected from the group consisting of: an aryl, a cycloalkyl, apartially unsaturated carbocycle, a heteroaryl, a heterocycloalkyl, anine to ten membered benzo-fused cycloalkyl, and a nine to ten memberedbenzo-fused heterocycloalkyl, wherein, the aryl, cycloalkyl, partiallyunsaturated carbocycle, heteroaryl, heterocycloalkyl, benzo-fusedcycloalkyl, or benzo-fused heterocycloalkyl, is optionally substitutedwith one or more substituents independently selected from: alkoxy,alkylamino, amino, cyano, dialkylamino, halogen, halogenated alkoxy,halogenated alkyl, halogenated —SO₂alkyl, halogenated thioalkyl,heteroaryl, hydroxy, hydroxy alkyl, —N(alkyl)C(═O)alkyl,—N(alkyl)C(═O)N(alkyl)₂, —N(alkyl)C(═O)NHalkyl, —N(alkyl)C(═O)Oalkyl,—N(alkyl)SO₂alkyl, —NHC(═O)alkyl, —NHC(═O)N(alkyl)₂, —NHC(═O)NH₂,—NHC(═O)NHalkyl, —NHC(═O)Oalkyl, —NHSO₂alkyl, nitro, —OC(═O)N(alkyl)₂,—OC(═O)NHalkyl, —SO₂alkyl, thio or thioalkyl; or an optical isomer,enantiomer, diastereomer, racemate, or pharmaceutically acceptable saltthereof; comprising

reacting a compound of formula (T5) with a compound of formula (T6), inan aprotic solvent, to yield the corresponding compound of formula (T3).